Main

Mantle-cell lymphoma (MCL) is a malignant lymphoma with unique morphologic, immunophenotypic, and molecular genetic findings.1234 The disease is characterized by generalized lymphadenopathy, with frequent involvement of the spleen, bone marrow, and gastrointestinal tract. The clinical course of patients with MCL is usually fatal despite initial responses to combination chemotherapy. Relapse of the disease is extremely frequent, occurring an average of 10 to 14 months after the completion of initial treatment. Some patients with MCL have been treated with high-dose therapy and autologous stem cell transplantation (autoSCT). However, preliminary reports show that relapse occurred in the majority of patients.567 Patients who relapse after autoSCT have a poor outcome, and the optimal treatment for these patients remains unclear. Several reports of allogeneic stem cell transplantation (alloSCT) in the treatment of poor prognosis non-Hodgkin's lymphoma relapsing after autoSCT have been published.89 We describe two patients with relapsed MCL after autoSCT successfully treated with alloSCT. Both patients remain alive and in complete remission 24 months after alloSCT.

Materials and methods

The diagnosis of mantle-cell lymphoma was established according to the currently accepted histologic, immunophenotypic and molecular criteria.12 Staging maneuvers at diagnosis included bone marrow biopsy, biopsy of extranodal sites whenever involvement was suspected, and thoracic and abdominal computed tomography. Post-therapy restaging included repetition of previously abnormal test and/or biopsies. For autoSCT peripheral blood stem cells (PBSC) were mobilized using cyclophosphamide 3 g/m2 and G-CSF 10 μg/kg/day. G-CSF-mobilized PBSC were also used as the stem cell source in alloSCT. Conditioning consisted of BEAM (BCNU 300 mg/m2 day −6, etoposide 200 mg/m2 and cytarabine 400 mg/m2 days −5 to −2, and melphalan 140 mg/m2 day −1) for autoSCT, and fractionated TBI 12 Gy days −7 to −4 plus cyclophosphamide 60 mg/kg days −2 and −1 for alloSCT. GVHD prophylaxis was with cyclosporin A and methylprednisolone.

Case 1

A 49-year-old woman was diagnosed as having a diffuse histologic variant of MCL Ann Arbor stage IVB in August 1994. The lymphoid cells expressed CD19 and CD5 and did not express CD23. The bcl-1 rearrangement was demonstrated by polymerase chain reaction (PCR). The serum LDH level was 573 IU/l (normal range: 250–450 IU/l) and the serum β2-microglobulin level was 2.9 mg/l (normal range: 1.1–2.8 mg/l). The patient was considered as being in the high–intermediate risk group according to the international prognostic index. She received nine courses of therapy with CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) achieving a partial remission (persistence of bone marrow infiltration). It was decided to proceed with high-dose chemotherapy with autologous PBSC transplantation in November 1995. Evaluation of the disease after autoSCT showed complete remission. Generalized relapse of the mantle-cell lymphoma was observed 2 years later. Serum levels of LDH and β2-microglobulin were both high (829 IU/l and 3.0 mg/l, respectively). Two courses of hyper-CVAD chemotherapy (cyclophosphamide, vincristine, adriamycin, dexamethasone, methotrexate, and cytarabine) were given as salvage therapy, resulting in a partial remission (persistence of bone marrow infiltration and abdominal lymphadenopathy). HLA typing revealed that the patient's brother was genotypically identical and she received an allogeneic unmanipulated PBSC transplant in May 1998. The Karnofsky performance status prior to alloSCT was 80%. No VOD occurred. On day 38, acute grade II GVHD was documented and treated with 2 mg/kg/day methylprednisolone. The patient developed extensive chronic GVHD with hepatic and oral mucosa involvement. With a follow-up of 24 months after alloSCT, the patient is alive in clinical and molecular complete remission of the disease. The Karnofsky score is 90%.

Case 2

Mantle-cell lymphoma was diagnosed in a 54-year-old male in May 1995. The diagnosis of MCL was based on characteristic cell morphology and immunophenotyping (CD5, CD19 and CD20-positive, and CD23-negative). The disease stage was IVA, with gastric and bone marrow involvement. The performance status was good, but the serum LDH and β2-microglobulin levels were high (624 IU/l and 4.3 mg/l, respectively). The patient was therefore considered as being in the high–intermediate risk group in the international prognostic index. He received two courses of hyper-CVAD, achieving a complete remission. An autologous PBSC transplant was undertaken in November 1996. Thirteen months after autoSCT the patient relapsed with diffuse lymphadenopathy, gastric, and bronchial involvement. The serum level of LDH was 508 IU/l and the serum level of β2-microglobulin was 4.1 mg/l. MINE (ifosfamide, mitoxantrone, and etoposide) and ESHAP (cisplatin, etoposide, cytarabine and methylprednisolone) therapy induced a second complete remission. HLA typing revealed that one brother was genotypically identical and the patient received an alloSCT in May 1998. The Karnofsky performance status prior to alloSCT was 80%. No VOD occurred. No acute GVHD was observed and cyclosporin A was stopped 6 months after alloPBSCT. Nine months after transplantation, chronic GVHD with skin and intestinal involvement was documented, responding favorably to prednisone and cyclosporin A treatment. With a follow-up of 24 months, there is no evidence of disease and the Karnofsky score is 90%.

Discussion

The long-term prognosis for patients with MCL is poor, with a median survival of approximately 4 years.34 Patients with MCL generally respond to their initial chemotherapy, with an overall response rate of 50–80% and a complete remission rate of 20 to 50%. Median duration of response is 1 to 3 years and virtually all patients relapse within 4 years.10 High-dose chemotherapy with autoSCT has an established role in the treatment of patients with relapsed lymphoid malignancies, and is being used increasingly for the initial treatment of poor prognosis malignant lymphoma.1112 A disease-free survival rate of 31% at 4 years has been reported after autoSCT in patients with MCL.7 However, there appears to be no plateau in the disease-free survival curve, with a significant number of relapses beyond 2 years.567 Patients who relapse after an autoSCT have a very poor outcome.

The potential benefits of alloSCT over autoSCT include the lack of tumor contamination of the graft and a graft-versus-tumor effect. The graft-versus-leukemia effect is well established in alloSCT. There is a significantly lower incidence of leukemia relapse in patients who undergo alloSCT compared with patients receiving autografts. A graft-versus-lymphoma effect has been suggested in patients with low-grade lymphoma in whom alloSCT appears to be associated with a lower risk of recurrence than autoSCT.1314 In this regard, it has been reported that the probability of relapse in patients with lymphoid malignancies is only 18% after alloSCT compared with 46% after autoSCT.15 There are limited data on the outcome of patients with MCL treated with alloSCT. Khouri et al6 have recently reported that both disease-free survival and overall survival at 3 years for alloSCT recipients were significantly higher compared with the autoSCT group. Clinical and molecular remissions after alloSCT in patients with resistant MCL have also been reported.1617 Therefore, the successful outcome after alloSCT in our patients may be attributed, at least in part, to a graft-versus-lymphoma effect. Another factor that could contribute to these results is the use of total body irradiation (TBI) in the conditioning regimen. Although there is no proof of the superiority of TBI-containing regimens, they could have a greater antitumor effect.18

There is little information regarding the outcome of alloSCT in patients who relapse after autoSCT.89 A high transplant-related mortality and incidence of severe GVHD have been reported in these patients. Experience with second transplants in acute leukemia suggests that both a longer interval between first and second transplant and a good performance status prior to the second procedure have a significant influence on survival.19 The same could be true in patients with malignant lymphoma. Our two patients developed late recurrence of the MCL after autoSCT (more than 1 year) and they underwent alloSCT at 32 and 18 months, respectively, after the first transplant. Before transplantation, both patients had a Karnofsky performance status of 80%. This observation suggests that alloSCT as salvage therapy after failed autoSCT in patients with MCL is feasible in selected cases. This procedure should be considered especially in patients with a good performance status and a prolonged disease-free survival after the first transplantation procedure.