1 Advanced Therapeutics Program, Toronto Sunnybrook Regional Cancer Centre, Sunnybrook and Womens College Health Sciences Centre, Toronto, Ontario; 2 University of British Columbia and the BC Cancer Agency, Vancouver, British Columbia; 3 Princess Margaret Hospital, Toronto, Ontario, Canada
Received 12 June 2003; revised 1 October 2003; accepted 29 October 2003
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ABSTRACT |
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The outcome of 20 patients with newly diagnosed mantle-cell lymphoma (MCL) treated on a prospective trial of autologous stem-cell transplantation (ASCT) and rituximab immunotherapy was compared with the outcome of 40 matched historical control patients treated with standard combination chemotherapy.
Patients and methods:
Control patients with MCL were identified from a lymphoma database, and pairs were matched with patients receiving ASCTrituximab for stage of disease, gender and age (±5 years). Only patients treated with an anthracycline- or cyclophosphamidefludarabine-based regimen were included.
Results:
Seventeen of 20 patients who received ASCTrituximab remain alive in remission at a median of 30 months from diagnosis; one patient relapsed 2 years post-ASCT, and two died at 7 and 11 months post-ASCT without evidence of lymphoma. Of 40 patients treated with conventional chemotherapy, with a median follow-up of 80 months, 33 have relapsed or progressed and 29 have died. Overall (OS) and progression-free (PFS) survival were superior in patients treated with ASCTrituximab compared with those treated with conventional chemotherapy (PFS at 3 years, 89% versus 29%, P <0.00001; OS at 3 years, 88% versus 65%, P = 0.052).
Conclusions:
This matched-pair analysis suggests that patients with advanced-stage MCL treated with ASCTrituximab had statistically significantly better PFS and a trend toward better OS than patients treated with conventional chemotherapy. Longer follow-up will determine response duration and the true impact of this treatment strategy on PFS and OS.
Key words: autologous stem-cell transplantation, mantle-cell lymphoma, matched-pair analysis, rituximab
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Introduction |
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We undertook a matched-pair analysis to compare the outcome of patients with MCL treated with ASCTrituximab in Toronto with that of a historical matched cohort of patients with MCL treated with conventional combination chemotherapy in Vancouver. Two historical randomly chosen control cases were matched to each study patient. Overall (OS) and progression-free (PFS) survival were compared. We present the results of this matched-pair analysis.
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Patients and methods |
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Response to therapy was assessed by serial clinical review, blood work, bone marrow aspirate, and biopsy and computed tomography scans of involved sites. These evaluations took place 8 weeks after ASCT, then every 3 months for the first year post-ASCT and every 6 months thereafter. Minimal residual disease (MRD) was evaluated by molecular analysis as follows. Morphologically positive baseline samples of lymph node, bone marrow (BM) or peripheral blood (PB) were assessed in all study patients by PCR for the presence of detectable BCL-1/JH rearrangements or clonal V(D)J rearrangements. Semi-nested PCRs were performed to allow a sensitivity level of approximately one diseased cell per 100 000 mononuclear cells. The BCL-1/JH junction was amplified with the external and internal primers listed in Table 1 [28]. In cases where BCL-1/JH was not established, an attempt was made to amplify clonal V(D)J sequences using consensus primers for VH framework regions, as detailed in Table 1 [28, 29]. Where possible, clonal V(D)J PCR products were then sequenced and analyzed with IgBLAST [30], and patient-specific primers for unique junction sequences were developed for use as internal primers in the semi-nested PCR assay. Serial molecular monitoring for minimal residual disease was performed on all follow-up BM and PB samples (pre-apheresis, pre-transplant and post-transplant, at 3- to 6-month intervals) in patients in whom a molecular marker was initially identified. The stem-cell graft was similarly evaluated for the presence of occult disease. DNA was extracted using Qiagen kits. For each time point, 500 ng of patient DNA was amplified in triplicate, and run along with a serially diluted positive control, DNA from a negative cell line and a sample with no DNA. All patient samples were also amplified with primers for the RAG2 gene to ensure the presence of good quality DNA.
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Clinical characteristics were abstracted from the database and by retrospective chart review. Pathology was determined by standard diagnostic criteria, including immunohistochemistry and flow cytometry. All samples were evaluated by immunological techniques for the presence of cyclin-D1 and/or t(11;14) by cytogenetics or fluorescence in situ hybridization. For the patients diagnosed and treated prior to 1992, cases were identified retrospectively.
Patients in the BCCA cohort were treated according to standard protocols using chemotherapy with or without involved field radiation therapy.
Study end points
Statistical evaluation compared OS and PFS in the ASCTrituximab group compared with the group treated with conventional chemotherapy. OS and PFS were defined according to the criteria of the International Workshop on Response Criteria [31], and were determined by the KaplanMeier method [32]. The significance of differences in actuarial survival was determined by the log rank method employing SPSS for Windows, version 10.1.
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Results |
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Patient characteristics are described in Table 2. Patients in the two groups were matched by design for disease stage, gender and age (±5 years), and relatively well matched for other features such as serum lactate dehydrogenase (LDH) level, degree of extranodal involvement and maximum tumor size. Of the 20 patients enrolled in the phase II study of ASCTrituximab, 12 were male and eight were female. Median age at diagnosis was 55 years (range 4165). Eighteen patients (90%) fell into the low or low-intermediate risk categories of the International Prognostic Index (IPI) at diagnosis. Seventeen patients (85%) had Ann Arbor stage IV disease, all with BM involvement by lymphoma. Other extranodal sites of involvement included peripheral blood (n = 4), colon (n = 1), lung (n = 1), liver (n = 1) and kidney (n = 1). Four patients had an elevated serum LDH level. All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The 40 matched historical controls (24 male, 16 female) had a median age of 57 years (range 3766). In contrast to the study patients, 11 of 40 control patients had an ECOG performance status of at least 2, a greater proportion had B-symptoms and seven patients had a high-risk IPI score.
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All 40 historical control patients received chemotherapy with or without radiation. Primary therapy was heterogeneous, but overall, all patients received treatment with an appropriate, usually anthracycline-based, multiagent chemotherapy regimen: VACOP-B (VP16, adriamycin, cyclophosphamide, vincristine, prednisone and bleomycin) (n = 13), CHOP (n = 12), ACOP-12 (adriamycin, cyclophosphamide, vincristine and prednisone) (n = 6), CPF (cyclophosphamide, prednisone and fludarabine) (n = 5), C-MOPP (cyclophosphamide, vincristine, procarbazine and prednisone) (n = 2) or chlorambucil plus prednisone (n = 2). Of the latter two patients, one has sustained a long-term remission and the other subsequently received CHOP. Ten patients also received radiation as part of initial therapy, and one patient received intrathecal chemotherapy. Thirty-four patients (85%) responded to primary therapy (21 CR, 13 PR). Two failed to respond, and four had progressive disease despite therapy. At the time of progression, 20 patients required treatment, which was individualized. Only one of the control cases has undergone treatment with high-dose chemo-radiotherapy and ASCT. This was carried out because of disease progressing despite CPF chemotherapy, and the patient has been in remission for 91 months since ASCT.
Toxicity data
A number of important toxicities were observed in patients treated on the phase II trial with ASCTrituximab. One patient experienced reactivation of hepatitis B during induction chemotherapy that was successfully treated with lamivudine. During the transplant period, 18 of 20 patients experienced febrile neutropenia. Mucositis occurred in 13 patients, and was of grade 3 severity in five. Two patients required brief transfers to the coronary care unit; one for atrial fibrillation with a rapid ventricular response, and one for chest pain and hypotension that resolved rapidly with volume resuscitation. There was no transplant-related mortality. In the post-transplant period, toxicities included six cases of interstitial pneumonitis, all felt to be related to BCNU, but one case was also likely related to treatment with amiodarone. The high incidence of interstitial pneumonitis prompted a dose reduction in BCNU from 500 to 450 mg/m2. There were no long-term pulmonary sequelae in the patients who developed pneumonitis. One patient experienced pneumocystis carinii pneumonia infection, five patients developed herpes zoster infection (one disseminated), there was one case of bilateral pneumonia requiring hospitalization, one case of cardiomyopathy that improved with supportive cardiac care and one prednisone-induced major depression. There were no significant infusion-related toxicities during rituximab administration, but two patients experienced transient neutropenia during treatment.
No formal toxicity data are available for the historical control patients.
Follow-up
With a median follow-up of 30 months (range 1447) from diagnosis and 25 months (range 641) from transplant, 17 of 20 patients on the phase II trial of ASCTrituximab remain alive and in first remission (16 in CR, one in CRu). One patient relapsed 24 months following ASCT and has progressed despite retreatment with two cycles of chemotherapy (fludarabine, mitoxantrone and rituximab). One patient died unexpectedly of a presumed cardiac event while in autopsy-documented CR 7 months post-ASCT, and one died of fulminant hepatic failure 11 months post-ASCT as a result of a second reactivation of hepatitis B 4 months following discontinuation of lamivudine therapy. This patient presented for medical attention after the onset of jaundice, and readministration of lamivudine was unsuccessful. Median PFS and OS have not yet been reached at 30 months in this patient population.
The matched control cases have been followed for a median of 80 months (range 23217) from diagnosis. Thirty-three of 40 patients progressed following primary therapy, and 29 patients have died. Median time to progression was 16 months (range 3183), and median OS was 46 months (range 6216). There was no difference in the PFS of the 31 control patients who received anthracycline as first-line therapy compared with the nine controls who received non-anthracycline therapy [median PFS 16 months (range 3184) versus 15 months (range 684), respectively]. As depicted in Figures 1 and 2, OS and PFS were superior in the study patients treated with ASCT and rituximab compared with those treated with conventional chemotherapy regimens (3 year PFS, 89% versus 29%, P <0.00001; 3 year OS, 88% versus 65%, P = 0.052).
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Results of molecular analysis
A molecular marker enabling serial PCR analysis has been identified to date in 14 of 20 patients treated on the phase II trial of ASCTrituximab. Five patients were followed for the BCL-1/JH rearrangement, and nine were followed for clonal V(D)J rearrangements (seven of these were more sensitively analyzed with patient-specific primers). Results are depicted in Figure 3. Although all 11 stem-cell grafts tested were PCR-positive, at 8 weeks post-ASCT, four of the patients with PCR-positive grafts were PCR-negative in the BM and eight were PCR-negative in the PB. Ten patients were in molecular remission in the BM at most recent follow-up. Interestingly, the one patient who relapsed 2 years post ASCT never attained PCR negativity in the BM, and reconverted to PCR positivity in the PB 6 months prior to clinical relapse.
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Discussion |
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There has been considerable interest in developing better treatment approaches for MCL. HDT-ASCT has been studied in patients with MCL, and mixed results have been reported [1425, 34]. ASCT appears to provide the greatest benefit when used up-front in newly diagnosed patients compared with at the time of relapse, whereas it is less successful for salvaging patients with relapsed disease [15, 21, 25, 43]. In general, HDT-ASCT is capable of inducing a high rate of CR, but current transplant strategies are not felt to be curative in most patients with MCL when used as a single modality. For these reasons, approaches aimed at enhancing the outcome from ASCT are under evaluation.
One such approach involves the use of purging strategies. A major concern in autografting patients is the reinfusion of stem-cell grafts contaminated by tumor cells that can potentially contribute to relapse post-transplant. A variety of ex vivo manipulations, such as CD34+ selection [14, 16, 25] or anti-B cell monoclonal antibodies [19, 25, 29], have been used in patients with MCL in order to try to purge stem-cell grafts of these malignant cells, but these strategies have met with limited success. In vivo purging techniques have included rituximab immunotherapy [44] or high-dose sequential chemotherapy [45], but the most successful approach has been with the use of both of these strategies in combination [46]. In a study by Magni et al. [46], seven patients with newly diagnosed MCL were treated with four doses of rituximab in combination with high-dose sequential stem-cell-supported chemotherapy (including high-dose cyclophosphamide, high-dose cytarabine, melphalan and mitoxantronemelphalan) in the hopes of achieving PCR-negative stem-cell products; in vivo purging was uniformly successful in all seven patients.
Our treatment strategy combined ASCT with both in vivo purging and post-transplant immunotherapy with rituximab. Rituximab was well tolerated and did not result in any serious adverse events. No late hematological toxicity was observed, although two patients developed transient neutropenia during treatment, which is a known potential complication [47]. It is uncertain whether rituximab contributed to the high incidence of interstitial pneumonitis observed post-transplant [48], but pneumonitis is a well described complication of BCNU chemotherapy, which is found in the CBV conditioning regimen [49]. We observed a higher than expected response rate to CHOP in our study patients (response rate 100%: 40% CR/CRu, 60% PR). However, in such a small sample size this could reflect the variability of patient response to chemotherapy.
This matched-pair analysis shows that patients with newly diagnosed advanced-stage MCL treated on the phase II trial of HDT-ASCT and rituximab had statistically superior PFS compared with historical control patients treated with conventional chemotherapy, and a trend toward better OS. Nevertheless, there were some limitations to the study design. The controls were a historical cohort of patients, making this a retrospective comparison. Although all patients in the matched case controls were treated with appropriate multiagent chemotherapy, their treatment was not entirely uniform. It is also difficult to compare treatment outcomes of regimens initiated many years ago with the therapeutic approaches of today. The matching of cases to controls resulted in relatively well-balanced features, but there was still an imbalance in clinical factors that may have prognostic significance in lymphoma, namely the IPI scores and ECOG perfomance status. In the ASCT group there was a lower frequency of patients with an IPI score of 4 or 5 compared with the conventional chemotherapy group. When we recalculated the PFS excluding the seven control group patients who had an IPI score of 4 or 5, the difference in PFS between treatment groups remained highly significant. This was true whether one compared treatment groups as a whole, or compared subgroups of patients with 01 IPI risk factors or those with 23 risk factors. These results indicate that the PFS difference observed between the two treatment groups did not result merely from the inclusion of more patients with adverse prognosis in the group receiving conventional chemotherapy, but that the improvement in PFS may well have been attributable to the intensive treatment plus rituximab maintenance. An additional safeguard against the possibility that our results simply reflect comparison to a control group with a poorer outcome is the observation that the median survival in our matched control cases was 42 months, substantially longer than the typical 3036 months reported in most series of patients with MCL treated with standard chemotherapy. Nevertheless, it is important to note that the follow-up time of the ASCT group was relatively short (25 months from transplantation), so these patients remain at risk of developing further late events, such as disease relapse.
Despite the limitations of our study, our results are in keeping with two other studies (one randomized controlled trial and one retrospective comparison) comparing the use of chemotherapy alone versus HDT and transplant in patients with MCL [25, 34]. In a study by Khouri et al. [25], 45 patients with MCL (25 previously untreated) were treated with the HCVAD regimen, followed by autologous or allogeneic stem-cell transplant. The authors compared the results of the 25 previously untreated patients who received HCVAD with those of a historical control group of 25 patients treated with a CHOP-like regimen. They found that 3 year event-free survival (EFS) and OS were superior in patients who received HCVAD plus stem-cell transplant compared with patients who received CHOP-like chemotherapy (3 year EFS, 72% versus 28%, P = 0.0001; 3 year OS, 92% versus 56%, P = 0.05) [25]. The European MCL Working Party has published early results of a randomized controlled trial comparing ASCT-HDT with interferon (IFN) maintenance in previously untreated patients who obtained PR or CR after chemotherapy with CHOP-like regimens [34]. A statistically significant benefit in PFS was observed in the ASCT arm compared with the IFN arm, with six of 46 (17%) relapses compared with 21 of 41 (53%) relapses seen at a maximum follow-up of 4 years (P = 0.0107), but no difference has been observed so far for OS (two versus six deaths, P = not significant) [34].
The clinical significance of molecular remissions in patients with MCL remains uncertain. In a study evaluating the use of rituximab plus CHOP in patients with newly diagnosed MCL, PCR-based analysis of MRD was not predictive of long-term outcome, as the few patients who achieved molecular remissions had similar PFS to those who did not [42]. In contrast, the studies correlating MRD status with clinical outcomes post-ASCT in MCL suggest that molecular status may be important, and that persistence or reappearance of detectable MRD after ASCT seems to be associated with a higher probability of relapse [29, 45]. In our study, the one patient who did not achieve PCR negativity in the BM and later reconverted to PCR positivity in the PB has been the only patient to relapse to date.
The initial results of our study suggest that OS and PFS were superior in the study patients treated with ASCT and rituximab compared with those treated with conventional chemotherapy regimens. Molecular as well as clinical remissions have been observed in the majority of evaluable patients treated with ASCTrituximab. We therefore conclude that this strategy combining HDT-ASCT with rituximab as both an in vivo purge and as post-transplant immunotherapy is a promising new treatment for MCL. Longer follow-up will determine response duration and the true impact of this treatment strategy on PFS and OS.
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FOOTNOTES |
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