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Frontline transplantation of autologous CD34+ selected blood cells for advanced mantle cell lymphoma: no evidence of long-term cure: a single centre experience
Patients with mantle cell lymphoma (MCL) are rarely cured with conventional therapy. Almost all patients inevitably relapse and median survival is only about 3 years.123 Intensification with high-dose chemotherapy (HDC) and autografting in first-line therapy has been thus proposed with encouraging results on early follow-up with EFS 70–80% at 24 or 3 years.5 However, due to the frequent BM involvement, its applicability seems to be compromised because lymphoma contamination of the graft could contribute to relapse. This is supported by some retrospective single centre studies.67 Here we report a retrospective analysis of a single centre experience with frontline HDC and purged autografts in order to intensify first-line therapy and to minimize the risk of graft contamination. Between January 1995 and December 1999 all patients with intermediate/high grade NHLs with BM involvement (ie state IV) at diagnosis were treated with high-dose chemotherapy (HDCT) and CD34+ selected PBSC transplantation.8 After re-reviewing, in eight patients, the histologically and immunophenotypically proven diagnosis of MCL according to the REAL classification was assigned to them.9 Eligibility diagnostic criteria had to be matched up to characteristic histological and immunophenotypical features as defined in the REAL classification.9 Cytogenetic or molecular genetic analyses were not done. BM involvement was defined by positive trephine biopsy examination only, regardless of the results of immunophenotypic or molecular genetic studies. These eight patients were transplanted between June 1995 and January 1999 and their characteristics are shown in Table 1 as well as bone marrow infiltration patterns. Median age was 45 years (range 37–52) and the male/female ratio was 3.0. There were no patients with morphological signs of PB involvement. Conventional induction chemotherapy consisted of anthracycline-containing chemotherapy (CHOP or third-generation regimens). For mobilizing PBSC as well as to decrease the tumor burden, the patients received cyclophosphamide 3 g/m2 and G-CSF (Neupogen; Hoffman-La Roche, Basel, Switzerland) within 1 month after completion of induction chemotherapy. Pre-transplant conditioning chemotherapy was by the BEAM regimen (carmustine 300 mg/m2, etoposide 800 mg/m2, Ara-c 1600 mg/m2 and melphalan 140 mg/m2) followed by infusion of immunoselected PBSC. CD34+ selection was performed using a computer-driven immunoaffinity column device (CEPRATE SC, CellPro, Bothell, WA, USA) according to the manufacturer's manual. Immunophenotypic and molecular genetic analyses (by PCR) of the grafts before and after the procedure were not done. Immunoselected grafts contained a median of 2.90 × 106/kg CD34+ cells (1.33–5.92) and prompt and uncomplicated engraftment was seen in all patients (the median time to ANC >0.5 × 109/l was 12 days, range 11–15, to platelets >20 × 109/l 16 days, range 14–21; data not shown). The treatment outcome and clinical follow-up are also given in Table 1. After induction chemotherapy one patient entered CR and the remaining seven PR only, all of them with residual BM involvement only (histologically defined). There was no residual lymph node or extranodal (other than BM) lymphoma involvement before mobilization chemotherapy. After HDC and transplantation all patients except one with persistent residual nodular BM infiltration, achieved CR. There was no treatment-related mortality. After a median follow-up of 38 months (range 15–59) three patients relapsed and the only one with PR progressed. This occurred from 3 to 22 months after transplantation and the sites of relapses are also shown in Table 1. The median progression-free survival (PFS) was 18 months and the median overall survival (OS) was not reached. One patient died of relapse, the remaining seven (88%) are still alive, with four (50%) of them still in continuous CR. The current OS is thus 88% and PFS 50%. Because of the insignificant power of this small group of patients and especially the non-randomized design (which makes the selection bias unavoidable) of our study, we are unable to draw any definitive conclusions concerning presented treatment strategy. However, our results contribute to the discussion concerning the utility of graft purging in MCL patients. Recently published papers have demonstrated the resistance of MCL cells to both in vivo10 and ex vivo purging6 as well as negligible clinical benefit of the latter strategy.7 Our limited data do not demonstrate the benefits of CD34+ cell selection and are thus in agreement with others testifying that, to date, there is no evidence that purging by any means could significantly influence disease-free survival.711 Interestingly, in spite of the persistent BM involvement before mobilization, only the above-mentioned patient with persistent BM infiltration after HDC progressed in the bone marrow. In the others, the relapse sites were either lymph nodes only (one patient) or lymph nodes with marrow simultaneously (two patients). As we did not assess the purging efficiency and because the sample size is small, it is impossible to conclude whether inadequate purging or inherent resistance of MCL to chemotherapy, or both, are major contributors to the treatment failures in our patients. In addition, we cannot exclude that we are presenting patients with poor prognostic factors because some authors suggest inability to maintain remissions in MCL patients with marrow infiltration at any time in the course of their disease.12 Possible survival benefits perceptible from our study must be interpreted cautiously because of inevitable selection bias and the small number of patients evaluated. In conclusion, first-line treatment of MCL with high-dose therapy may improve prognosis of advanced MCL but graft manipulation in order to minimize lymphoma contamination seems to add little benefit in this setting.
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Jindra, P., Koza, V., Švojgrová, M. et al. Frontline transplantation of autologous CD34+ selected blood cells for advanced mantle cell lymphoma: no evidence of long-term cure: a single centre experience.
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