Autologous stem cell transplantation for ... - Wiley Online Library

British Journal of Haematology, 2000, 109, 736±742

Autologous stem cell transplantation for anaplastic large-cell lymphomas: results of a prospective trial E. Deconinck, 1 T. Lamy, 2 C. Foussard, 3 F. Gaillard, 4 V. Delwail, 5 P. Colombat, 6 P. Casassus, 7 A. Lemevel, 8 A. Brion 1 and N. Milpied 4 for the Groupe Ouest-est d'Etude des LeuceÂ mies et Autres Maladies du Sang (GOELAMS) 1 Department of Haematology, Jean Minjoz University Hospital, BesancËon, 2 Ponchailloux University Hospital, Rennes, 3 University Hospital, Angers, 4 Hotel-Dieu University Hospital, Nantes, 5 University Hospital, Poitiers, 6 Bretonneau University Hospital, Tours, 7 Avicenne Hospital, Bobigny, and 8 Gauducheau Anti-cancer Centre, Rennes, France Received 5 November 1999; accepted for publication 22 February 2000

Summary. Autologous stem cell transplantation (ASCT) in the front line treatment of non-Hodgkin's lymphoma (NHL) remains controversial. Anaplastic large-cell lymphoma (ALCL) is known to have its own clinical and biological features. The outcome of ALCL patients treated with highdose chemotherapy and ASCT as part of their first-line therapy was analysed in 202 intermediate or high-grade NHL patients in a prospective randomized trial. First-line chemotherapy comprised two alternating anthracyclinecontaining regimens. Responding patients were autografted after a BEAM (BCNU, cytarabine, etoposide and melphalan) regimen. Patients with bulky or residual masses were irradiated. Fifteen patients with ALCL were identified by morphological and immunological features (CD30 was expressed in 14 out of 15 patients, three patients expressed B-cell markers, five patients expressed T-cell markers and seven patients did not express cell markers). Anaplastic lymphoma kinase (ALK) expression was confirmed in seven cases. The median age was 39 years with a predominant

male sex ratio (2´75). Thirteen patients were stage $ III and six presented with two or more adverse prognostic factors. According to the international age-adjusted prognostic index, the expected complete remission (CR), event-free survival (EFS) and overall survival (OS) rates were 69%, 71% and 69%. Two deaths were observed (one due to interstitial pneumonitis, one due to pulmonary carcinoma). All patients entered CR, no relapse occurred and EFS and survival reached 87% with a follow-up of more than 5 years. These results differ significantly from those observed in the other 176 lymphoma patients: event-free survival was only 53 ^ 5% and OS reached 60 ^ 4% with a median follow-up of 56 months (P 0´006). Intensified chemotherapy with autologous stem cell support appeared effective in the treatment of ALCL, offering patients the real chance of a cure.

In terms of prognosis for non-Hodgkin's lymphoma (NHL) patients, histological classification remains the major setting by differentiating low- and intermediate to high-grade NHL (The Non-Hodgkin's Lymphoma Classification Project, 1982). In this latter group, the histological subtype does not appear to have a major impact on the clinical outcome (The International Non-Hodgkin's Lymphoma Prognostic Factors Project, 1993). Nevertheless, in recent years several entities have become more accurately identified as having their own clinical outcome with specific prognostic features, e.g. mantle cell, some T-cell and anaplastic large-cell

lymphomas (ALCLs) (Stansfeld et al, 1988; Harris et al, 1994; The Non-Hodgkin's Lymphoma Classification Project., 1997). ALCLs were described and individualized among the group of diffuse large-cell lymphomas as presenting a proliferation of anaplastic large cells characterized by the presence of a specific surface membrane antigen, Ki-1 (CD30) (Stein et al, 1985, 1991). Currently, the definition of ALCL is more accurately based on the presence of a specific chromosomal abnormality, t(2,5)(p23;q35), or the detection of the corresponding fusion gene (NPM±ALK) and its chimaeric protein counterpart the anaplastic lymphoma kinase (ALK) (Mason et al, 1990; Shiota et al, 1994; Lamant et al, 1996; Sarris et al, 1996). In a GELA (Groupe d'Etude des Lymphomes de l'Adulte) study, ALCLs clearly appeared to have a better prognosis than other NHLs (Tilly et al,

Correspondence: E. Deconinck, Service d'HeÂmatologie, HoÃpital Jean Minjoz, CHU, 25030 BesancËon Cedex, France. E-mail: edeconinck@ chu-besancon.fr

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Keywords: anaplastic, diffuse large-cell lymphoma, CD30, autologous stem cell transplantation, prognostic factor.

q 2000 Blackwell Science Ltd

ASCT for Anaplastic Large-Cell Lymphomas 1997). One previous report mentioned a 100% complete remission (CR) rate and survival for a group of 16 consecutive ALCL patients autografted as their first line of treatment (Fanin et al, 1996). These results call into question the role of intensified chemotherapy, especially in the case of highly chemosensitive tumours, which is probably the best setting in which to test this hypothesis. Data in the literature provide a favourable outcome concerning the place of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) in chemosensitive NHL relapses and in a subgroup of untreated lymphomas with some initial adverse prognostic features (Shipp et al, 1999), but the use of ASCT in first-line treatment of the majority of NHL cases is still controversial (Haioun et al, 1994, 1997; Milpied et al, 1994; Shipp et al, 1999). This report focuses on the favourable results obtained in a homogeneous group of 15 ALCL patients autografted in their first-line treatment during a prospective randomized trial. PATIENTS AND METHODS Patients. Between 1990 and 1994, the Groupe Ouest-est d'eÂtude des LeuceÂmies et Autres Maladies du Sang (GOELAMS) conducted a prospective randomized trial: 202 patients, aged from 15 to 60 years, with newly diagnosed intermediate or high-grade NHL (F, G and H of the Working Formulation) were consecutively recruited by 22 French haematological centres. Fifteen (8%) ALCLs were identified among the 191 assessable lymphoma patients (Milpied et al, 1994, 1996). Patients with a positive human immunodeficiency virus (HIV) serology, a concomitant or previous cancer (except in situ cervix or skin carcinomas), uncontrolled heart or pulmonary disease or those with kidney or liver failure were not included. The competent ethical committee (CCPPRB of Pays de Loire) approved the protocol design. Informed consent was obtained from all eligible patients before inclusion. The investigators followed the protocol guidelines in accordance with the precepts of the Helsinki Declaration. Pathological and immunological studies. Lymphomas were classified according to the Working Formulation and the Updated Kiel Classification for newly individualized entities (The Non-Hodgkin's Lymphoma Classification Project, 1982; Stansfeld et al, 1988). The criteria to define ALCLs were previously described; briefly, the diagnosis of ALCL was based on the proliferation of large cells with anaplastic morphology (pleomorphic nuclei, prominent nucleoli and abundant cytoplasm) and the expression of the CD30 antigen on the surface of the lymphoma cells (Stein et al, 1985, 1991; Delsol et al, 1988). Retrospectively, all samples were tested for ALK expression by additional immunophenotyping. Slides from routinely paraffin-embedded tissues were stained with haematoxylin±eosin, Giemsa and Gordon± Sweet. A phenotypic study was performed on paraffin sections using immunoperoxidase labelling with paraffinsuitable antibodies: CD45/LC (leucocyte common antigen, M0701; Dako, Glostrup, Denmark), CD30/Ber H2 (M0751; Dako) or CD30/HSR4 (Immunotech, Marseilles, France),

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CD20/L26 (M0786; Dako), BNH9 (MO743; Immunotech), DBB42 (Immunotech), CD45RO/UCHL1 (M0742; Dako), CD3/anti-CD3 epsilon chain polyclonal antibody (A0452; Dako), EMA/E29 (epithelial membrane antigen, M0613; Dako) and ALK1 (M7195; Dako). Additional phenotyping with CD68/KP1 (M0814; Dako) and CD15 (Immunotech) was carried out on frozen sections in six cases of anaplastic morphology. For all included patients, the diagnosis was confirmed and revised by three different pathologists, with 100% confidence of agreement for ALCL and 80% (141of 176 revised) for other lymphoma subtypes. Lymphoma staging. Initial extension of the lymphoma was defined after clinical, radiological and biological examinations as defined below. Medical history, clinical examination of all accessible adenopathy sites (comprising the oropharyngeal sites), thoracoabdominopelvic tomodensitometry, ultrasonographic exploration of the liver and spleen, chest radiograph, lactate dehydrogenase (LDH) and b2-microglobulin serum levels, and marrow and lymph node histology with immunological staining were obtained for all patients. Stage was defined according to the Ann Arbor classification (Carbone et al, 1971). To enter the study, patients had to have at least stage II with an abdominal bulky disease (. 10 cm length in one dimension) or stage III or IV extensive disease. Performance status was assessed according to the ECOG scale. Prognostic factors were classified according to the International Prognostic Index (IPI), adjusted for age and based on LDH level, performance status and tumour stage (The International Non-Hodgkin's Lymphoma Prognostic Factors Project, 1993). Protocol design. Treatment started with a CEP chemotherapy course (cyclophosphamide 750 mg/m2 on day 1, vindesine 3 mg/m2 on day 1, prednisone 50 mg/m2 on days 1±5). The induction scheme comprised two different chemotherapy schedules A and B, beginning on day 8 of the CEP cycle. A (CEEP) consisted of cyclophosphamide 750 mg/m2 on day 2, vindesine 3 mg/m2 on days 1 1 5, epirubicine 100 mg/m2 on day 2, prednisone 50 mg/m2 on days 1±5; and B (MINE) consisted of methotrexate 100 mg/m2 on day 1, ifosfamide 1500 mg/m2 on days 1±3, mitoxantrone 10 mg/m2 on days 1 1 2, etoposide 150 mg/m2 on days 1±3. In accordance with the initial randomization, patients received either the AABB or ABAB sequences. Response was evaluated after the two first induction courses and at the end of the sequence. Response criteria were as follows: complete remission (CR) was disappearance of all signs of disease; very good partial response (VGPR) was regression . 75% of all measurable target volumes and disappearance of marrow involvement; partial remission (PR) was regression . 50% of all measurable target volumes and/or persistence of marrow involvement; stable disease (SD) was regression # 50% of measurable disease; and progressive disease (PD) was the appearance of a new lesion or progression . 25% of pre-existing lesions. Patients in CR, VGPR or PR continued with the planned scheme. Patients in SD or PD received a salvage regimen (cytarabine 2000 mg/ m2 on days 1±3, etoposide 100 mg/m2 on days 1±5, cisplatinum 20 mg/m2 on days 1±5).

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E. Deconinck et al male sex ratio (2´75). Thirteen of the 15 ALCL patients were stage $ III and 6 out of 15 patients (40%) had more than two adverse prognostic factors, according to the IPI. A bulky disease $ 10 cm was found in five patients (33%), a large mediastinum in three cases. Skin and marrow involvement was identified in two and three cases respectively. By definition, all lymphoma cells expressed CD30, except in one case, but histological and cytological features were characteristic of ALCL. The expression of pan-T and pan-B markers was found in five and three cases respectively. EMA was present in nine cases, CD15 in three and CD45 and BerH2 in two patients. Five cases (33%) belonged to the T-cell lineage, four (27%) to the B-cell lineage and six cases (40%) exhibited a null phenotype, but in three cases (20%) immunological staining remained incomplete and insufficient to definitely assign a clear phenotype to the lymphoma cells. In another case with a null phenotype, the T-cell receptor was rearranged and this case then exhibited a T-cell genotype. ALK expression was found to be positive in four out of five T cases, in three out of six null cases (but two were non-evaluable) and negative in all B cases. Eleven patients (73%) achieved CR or PR before ASCT, one after the salvage regimen. Four patients were grafted with a stable disease, one after receiving the salvage regimen. No patients were progressive before autografting, all were in clinical CR after ASCT and five (33%) received the planned irradiation. The follow-up reached 5 years for 12 patients. Two deaths occurred in CR patients, one 8´5 months after ASCT (from interstitial pneumonitis) and the other 15 months after ASCT (from a metastatic pulmonary carcinoma). No relapse was observed in the 13 surviving patients and all remained in first CR with a median follow-up of 68 months (range 56±77) (Table II).

Bone marrow (BM) or peripheral blood stem cells (PBSCs) were collected in responding patients after the third or fourth chemotherapy cycle. BM was harvested after haematopoietic recovery and PBSCs during the haematopoietic recovery with granulocyte colony-stimulating factor (G-CSF) priming. An ASCT was performed 120±150 d after the randomization. The conditioning regimen BEAM included BCNU 300 mg/m2 on day 1, continuous infusion of cytarabine 400 mg/m2 on days 1±4, etoposide 400 mg/ m2 on days 1±4 and melphalan 140 mg/m2 on day 6, with the reinfusion of stem cells on day 8. No haematopoietic growth factor was systematically administered after transplantation. Patients with an initial bulky disease or persistent residual masses were irradiated just before starting the conditioning regimen or between days 60 and 90 after transplantation (20 Gy in 10 d). A final evaluation, identical to the initial one, was performed 2±3 months after the end of treatment. Statistical analysis. Data were computed using SPSS software (SPSS software, Chicago, IL, USA). Dates were calculated from the date of randomization to the date of disease progression, relapse or death. The survival curves were established using the Kaplan and Meier method and compared with log-rank tests (Kaplan & Meier, 1958). Differences were regarded as significant if the two-sided P-value was less than 0´05. Data collection was closed in December 1996 and updated in July 1998. RESULTS ALCL patient characteristics The major clinical and biological features are presented in Table I. The median age was 39 years with a predominant

Table I. Patients' characteristics at diagnosis. Patient no.

Age/gender

Immunophenotype

ALK

Stage

Status (ECOG)

BM

Visceral involvement

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

18/M 55/F 31/F 38/M 27/M 19/F 45/M 55/M 58/M 41/M 45/F 33/M 25/M 39/M 45/M

Null* Null* nUll Null T B B Null* B T T T B T Null

1 ± 1 NE 1 ± ± NE ± 1 ± 1 ± 1 1

IV III III IV III IV III IV II II III IV IV IV IV

1 0 1 1 3 3 3 1 2 1 1 1 1 1 4

1 ± ± 1 ± ± ± ± ± ± ± ± ± 1 ND

Skin, digestive tract None None Lung None Lung None Liver, spleen None None None Lung, pleural Lung Skin Lung, liver, CNS

LDH

Bulk (cm)

Risk factors (IPI)

N N A N A N A N N N N N A N N

10 5 0 10 5 10 0 10 0 0 10 0 0 0 10

1 1 2 1 3 2 3 1 0 0 1 1 2 1 2

BM, marrow involvement; N, normal; A, superior to normal; ALK, anaplastic lymphoma kinase expression; NE, non-evaluable; ND, not done; LDH, lactate dehydrogenase. *Immunophenotype was incomplete (see text). q 2000 Blackwell Science Ltd, British Journal of Haematology 109: 736±742

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Table II. Outcome and treatment characteristics of the ALCL patients. Patient no.

Response to induction

Salvage regimen

Source of HSC

Radiotherapy

Follow-up (months)

Outcome

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

CR CR CR PR ST VGPR VGPR PR ST CR VGPR CR VGPR ST ST

No No No No No No No Yes No No No No No No Yes

PBSC PBSC BM BM PBSC BM BM BM BM PBSC BM BM BM BM PBSC

Yes No No No Yes Yes No Yes No No No No No No Yes

77 72 71 73 69 8´5 68 72 60 63 15 61 60 62 56

CR1 CR1 CR1 CR1 CR1 Death CR1 CR1 CR1 CR1 Death CR1 CR1 CR1 CR1

HSC, haematopoietic stem cells.

Event-free survival (EFS) and overall survival (OS) were 87 ^ 6% (Fig 1). Comparison between ALCL and non-ALCL patients Among the 176 other lymphoma patients, 118 (67%) were autografted in first CR or PR and 14 (12%) received the salvage regimen. Fourteen patients died before the transplantation procedure and 43 other patients were not grafted because of progressive disease, patient refusal or failure of stem cell collection. Twenty relapses (17%) were observed at 6 months after transplantation. Event-free survival was 53 ^ 5% and OS reached 60 ^ 4% with a median followup of 56 months (range 2±65). The difference in survival curves between ALCL and non-ALCL patients was significant (P 0´006; Fig 1).

Fig 1. Survival of ALCL and other NHL patients. For ALCL patients, EFS OS. The difference in survival between ALCL and non-ALCL patients was significant, P 0´006.

DISCUSSION These results present a series of 15 ALCL patients treated homogeneously with third generation chemotherapy regimens, followed by an intensified treatment with autologous stem cell support. In accordance with the incidence of ALCLs in previous studies (2±22% of the large-cell lymphoma patients), our sample represented 8% of the whole lymphoma population studied (Chott et al, 1990; Greer et al, 1991; Fanin et al, 1996; Tilly et al, 1997). The major characteristics of ALCL were present, i.e. the cutaneous involvement or male predominance, but the clinical presentation was usually severe, with six patients (40%) having an IPI that was intermediate to high (2) or high (3) and six an initial bulky disease. The usual phenotype spectrum (B, T, null) was present (Greer et al, 1991 Shulman et al, 1993; Kadin, 1994; Romaguera et al, 1994; Tilly et al, 1997). The null phenotype is probably overestimated because there were only a few antibodies present at that time suitable for labelling on paraffin-embedded tissues and enhancement of labelling techniques, i.e. microwaving, was not routinely performed (Delsol et al, 1988). The diagnosis of ALCL could be considered to be insufficiently accurate because of the lack of karyotypic and molecular analyses, but these tests were not routinely available at the time of the study and the specific abnormalities had not yet been clearly individualized. The t(2,5)(p23;q35) and its presence in T-cell ALCL was first described by Mason et al (1990). The fusion gene NPM±ALK was cloned in 1994 and monoclonal antibodies against the chimaeric anaplastic lymphoma kinase have only been available since 1996 (Lamant et al, 1996; Sarris et al, 1996). In the REAL classification, only T ALCL was individualized as a distinct entity, null ALCL was considered as a subtype of this and B ALCL as a part of the B large-cell


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E. Deconinck et al

lymphomas (Harris et al, 1994). The relevance and specificity of these features are currently under investigation and retrospective analyses of our material cannot take into account these new data. Nevertheless, all the histopathological samples, with or without morphological and immunological features of ALCL (Delsol et al, 1988; Filippa et al, 1996), were confirmed by a consensual review of at least three pathologists. The expression of the ALK protein was retrospectively confirmed by immunophenotyping in 7 out of 11 T or null cases, two other null cases remained inconclusive and six samples were negative (two null and all B cases). This ALK expression was probably underestimated in some samples because of deterioration after preservation. We concluded that all T cases were true ALK 1 T-ALCL, a doubt persisted for two null cases and the remaining (B and some null cases) will probably currently be reclassified as diffuse large B-cell lymphomas (Harris et al, 1994). According to the IPI and the distribution of our series, the expected CR, disease-free survival (DFS) and OS were, respectively, 69%, 71% and 69% at 2 years (The International Non-Hodgkin's Lymphoma Prognostic Factors Project, 1993). There was a 100% CR rate after autografting, whereas only 12 patients responded to the initial chemotherapy scheme with or without the salvage regimen. Four patients who failed to respond to the first chemotherapy schedule obtained a CR after the myeloablative regimen, giving some evidence of the role of dose intensity. The DFS and OS finally reached 87% at 5 years. For all but one surviving patient, the observation time was longer than 5 years and these patients can be considered to be cured. One of the observed deaths was directly due to the intensive procedure (interstitial pneumonitis). The second (a pulmonary cancer occurring less than 1 year after the diagnosis of lymphoma) was a concomitant disease rather than a direct complication of the intensification procedure. The role of radiation therapy remained difficult to analyse. Five of the six patients with a bulky disease were irradiated (involved field radiotherapy) and this fact must be taken into account even if relapses generally occurred outside the initial tumour sites. No relapse was observed in our patients, whereas the expected relapse rate was theoretically 20±30%, occurring mainly during the first 2 years after the end of treatment. In the literature, CR rates for ALCLs treated with chemotherapy ranged from 30% to 92% with OS and DFS achieving 29±77% and 50±67% respectively (Chott et al, 1990; Greer et al, 1991; Nakamura et al, 1991; Shulman et al, 1993; Kadin, 1994; Pileri et al, 1994; Reiter et al, 1994; Romaguera et al, 1994; Clavio et al, 1996; Zinzani et al, 1996; Tilly et al, 1997). In the largest series of 146 cases, OS was 66 ^ 8% at 5 years and the initial CR rate reached 75%, but the DFS was not reported (Tilly et al, 1997). In all of these studies, treatment was based on CHOP (cyclophosphamide, hydroxydoxorubicin, vincristine and prednisone)-like or third generation chemotherapy regimens with, occasionally, HDC and ASCT in first response. None of these reports clearly studied the role of systematically reinforcing chemotherapy with the use of an autologous stem cell support. One study mentioned 16

consecutive cases of ALCL autografted in front-line therapy (Fanin et al, 1996). Impressive results were obtained: 100% DFS and OS at a median of 45´5 months of follow-up. Together with ours, these results constitute a series of 31 ALCL patients grafted systematically in first response after an intensive chemotherapy regimen and involved field radiation of bulky or residual masses with OS and DFS reaching 93´5 ^ 4% with no relapse after transplantation. In a retrospective study by the European Bone Marrow Transplantation (EBMT) group, the same author reported 64 cases of T-cell ALCLs autografted during their treatment course, but the heterogeneity of the patients (adults and children) and the therapeutic schedules could not provide a clear description of the role of ASCT (Fanin et al, 1999). Two deaths occurred during our study and it must be kept in mind that ASCT, despite being a safe procedure, exhibited a 2±5% mortality rate. This toxicity is probably lower today with the clinical development of haematopoietic growth factors and peripheral blood stem cell transplantation (Fanin et al, 1999). Our study confirms that ALCL is a particular entity, with a better prognosis than other NHLs even if all patients were autografted systematically after an intensified chemotherapy regimen. Anaplastic morphology with CD30 expression in NHL patients had clearly been demonstrated to have an independent prognostic value, whatever the ALK expression (Tilly et al, 1997). Recently, the T and null CD301 ALCLs were reanalysed according to the expression of ALK, showing that ALK1 patients exhibited a better prognosis than ALK2 patients (Falini et al, 1999). In the future, ALCLs will be more accurately defined from a karyotypic and molecular point of view. These data question the role of the histopathological classification as a major and independent prognostic factor in the group of socalled intermediate and high-grade lymphomas. Our results and those from others (Fanin et al, 1996, 1999) also tend to demonstrate that ASCT offers ALCL patients a 90% chance of obtaining a long remission or a probable cure with an acceptable toxicity and no relapse. This is probably one of the best treatments available today. A more definite answer can be obtained only by a prospective randomized trial. It would seem logical to presume that highly chemosensitive tumour cells, such as those in ALCL, react better to intensified treatments, whereas in less sensitive tumours this advantage of chemotherapy intensification is not obvious. REFERENCES Carbone, P.P., Kaplan, H.S., Musshoff, K., Smithers, D.W. & Tubiana, M. (1971) Report of the committee on Hodgkin's disease staging classification. Cancer Research, 31, 1860±1861. Chott, A., Kaserer, K., Augustin, I., Vesely, M., Heinz, R., Oehlinger, W., Hanak, H. & Radaszkiewicz, T. (1990) Ki-1 positive large-cell lymphoma. A clinico-pathologic study of 41 cases. American Journal of Surgical Pathology, 14, 439±448. Clavio, M., Rossi, E., Truini, M., Carrara, P., Ravetti, J.L., Spriano, M., Vimercati, A.R., Santini, G., Canepa, L., Pierri, I., Celesti, L., Miglino, M., Castellaneta, A., Damasio, E. & Gobbi, M. (1996)


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