High-dose CT with Stem Cell Reconstitution in Mantle Cell Lymphoma
High-dose CT with Stem Cell Reconstitution in Mantle Cell Lymphoma
Abstract & CommentarySynopsis: Autologous peripheral blood stem cell transplantation performed in previously treated patients with stage IV mantle cell lymphoma resulted in a four-year overall survival of 92% and a disease-free survival of 76%.
Source: Haas R, et al. Leukemia 1996;10:1975-1979.
Mantle cell lymphoma is an entity that has been recognized as such for only the last 15 years or so. In the past, it was considered a diffuse, small lymphocytic lymphoma with which it shared some morphologic and immunophenotypic characteristics (e.g., CD5+). In the Working Formulation, most of the mantle cell lymphomas were classed as diffuse, small cleaved cell lymphomas, although some of these cases were placed in five different Working Formulation categories. However, mantle cell lymphoma is associated with a characteristic chromosomal translocation, t(11;14), in which the cyclin D gene is brought under the transcriptional influence of the immunoglobulin heavy chain gene. Overexpression of cyclin D is generally not by itself a transforming event. However, more recently, mantle cell lymphomas have been found to often contain alterations in p16 and other cyclin-dependent kinase inhibitors, such that the molecular pathogenesis can be viewed as both an overexpression of cyclin D and the removal of the natural brake to cyclin action.Mantle cell lymphoma can also be characterized as a discrete clinical entity. The disease usually occurs in older people (median age, 64), often presents in advanced stage, with gastrointestinal involvement a common extranodal site of disease, and the disease is often refractory to treatment. The response rate to conventional chemotherapy is lower than expected, and the overall survival is very poor.1 Indeed, most workers consider mantle cell lymphoma to be an aggressive histology lymphoma, though unlike other aggressive histology lymphomas, the possibility of cure with conventional dose combination chemotherapy seems more remote.
The humanized anti-CD20 antibody in phase III testing from IDEC Pharmaceuticals appears to have significant single-agent activity in mantle cell lymphoma; however, long-term follow-up data are not available yet. High-dose therapy with autologous stem cell transplantation has been attempted in small series of patients with results that appear superior to conventional dose combination chemotherapy, but still without a clear plateau on the survival curve.
Haas and colleagues at the Universities of Heidelberg and Essen presented their experience using high-dose chemoradiotherapy in 13 patients with stage IV mantle cell lymphoma who were in first partial (five patients) or complete (four patients) remission or relapsed disease in second complete or partial remission (four patients). All patients had been treated with at least two previous chemotherapy regimens, receiving between four and 15 cycles of treatment. One patient had received local radiotherapy. Criteria for the diagnosis of mantle cell lymphoma included morphologic and flow cytometric criteria (CD19, CD20 positivity, and CD5 positivity, except in a single patient). The patients ranged in age from 32-60 years (median age, 49 years). The bone marrow was involved with tumor in seven of the 13 patients.
All patients were treated with cytarabine 2 grams/m2 every 12 hours on days 1 and 2, and mitoxantrone 10 mg/m2 on days 2 and 3. Filgrastim (G-CSF) 300 mg/m2 was started on day 4 and continued until leukapheresis. Peripheral blood stem cells were collected as early as day 11 and as late as day 28. One to four leukaphereses were required to harvest a sufficient number of CD34+ cells. The harvested product was CD19-negative in five cases, and in the remainder, the percentage of CD19-positive cells ranged between 0.05-2.91%.
After stem-cell mobilization chemotherapy, eight patients were in complete remission, five were in partial remission, and one had relapsed. The patient in relapse and the five in partial remission were given a second course of cytarabine and mitoxantrone and all went into complete remission. Patients went on to high-dose chemoradiotherapy a median of 15 weeks after stem-cell mobilization (range, 6-24 weeks). The conditioning regimen consisted of 14.4 Gy total body irradiation hyperfractionated over four days, and a total dose of 200 mg/kg cyclophosphamide given over four days. The patient who had previously received radiation therapy was conditioned with BEAM combination chemotherapy (BCNU, etoposide, cytarabine, melphalan).
One patient died of interstitial pneumonitis on day 17. Two patients relapsed at 10 and 11 months; both of these patients were transplanted in second complete remission. With a median follow-up time of 18 months, the remaining 10 patients remain alive in complete remission (range, 10-47 months). The four-year disease-free survival was 76% and the overall survival was 92%.
COMMENT
This study has some obvious limitations. There is a strong selection bias. The median age of patients on this study is 15 years younger than the median age of an unselected population. In addition, all the patients on this study had responded at least once and sometimes twice to combination chemotherapy regimens. In my experience, this is a particularly unusual subset. Many patients with mantle cell lymphoma are refractory to primary treatment and those that aren’t are usually refractory to salvage treatment. Thus, it should not be concluded from the paper that three-fourths of patients with mantle cell lymphoma are curable with high-dose therapy. However, the paper may add impetus to study the use of high-dose therapy earlier in the course of patients who are hearty enough to go through autologous stem cell transplantation.Therapeutic options for mantle cell lymphoma are limited. Remissions induced by CHOP or other anthracycline-containing combination regimens are generally not as frequent or as durable as remissions obtained with the same regimens in diffuse large cell lymphoma.1-5 Paclitaxel is marginally effective against mantle cell lymphomas.6 Complete remission rates are 50-60% but the average remission duration is less than two years and the median survival is usually 3-4 years. Interpretation of some of the data are complicated by the inclusion of some cases of the vaguely nodular variant of mantle cell lymphoma, which may behave in a more indolent fashion.7
Mantle cell lymphoma accounts for about 6-8% of all lymphomas. It is the form of lymphoma that is most refractory to treatment. New approaches to its management are needed. A thorough evaluation of the efficacy of high-dose therapy with autologous stem cell support is warranted.
References
1. Fisher RI, et al. Blood 1995;85:1075-1082.2. Teodorovic I, et al. J Clin Oncol 1995;13:2819-2826.
3. Zucca E, et al. Leuk Lymphoma 1994;13:105-110.
4. Criel A, et al. Proc Am Soc Clin Oncol 1992;11:A1163.
5. Shivdasani RA, et al. J Clin Oncol 1993;11:802-811.
6. Younes A, et al. J Clin Oncol 1995;13:583-587.
7. Weisenburger DD. Leukemia 1991;5 (suppl 1):26-39.
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