1 Department of Internal Medicine, Division of Oncology/Hematology, and 2 Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
* Correspondence to: Dr J. O. Armitage, Department of Internal Medicine, Division of Oncology-Hematology, 987680 Nebraska Medical Center, Omaha, NE 68198-7680, USA. Tel: +1-402-559-7290; Fax: +1-402-559-8597; Email: joarmita{at}unmc.edu
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Abstract |
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Methods: Ninety-seven patients, (80 patients-autologous; 17 patients-allogeneic) who received a HSCT for mantle cell lymphoma were included in the study.
Results: The complete response rates at day 100 between the two groups were similar (73% vs. 62%). Day-100 mortality was higher in the allogeneic HSCT group (19% vs. 0%) (P < 0.01). The estimated 5-year relapse rates, 5-year event-free survival (EFS) and 5-year OS among the allogeneic HSCT patients were 21%, 44% and 49%, respectively, similar to 56%, 39% and 47% in the autologous group. Ten patients received HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone + high-dose methotrexate and cytarabine) ± rituximab prior to transplant. There have been no relapses or deaths amongst these patients at a median follow-up of 16 months.
Conclusions: Patients treated with allogeneic HSCT had a lower relapse rate, but similar EFS and OS to autologous HSCT. Treatment of MCL with HyperCVAD ± rituximab followed by HSCT seems promising.
Key words: mantle cell lymphoma, autologous hematopoietic stem cell transplantation, allogeneic hematopoietic stem cell transplantation, HyperCVAD
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Introduction |
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The response rates and overall survival in patients with MCL are poor. Fisher et al. [3], in their study of 36 patients with MCL, estimated an 8% 10-year failure-free survival, which was significantly lower than the other types of lymphomas. Multiple chemotherapeutic regimens have been used for MCL, including CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) [5
], fludarabine [6
], fludarabine and idarubicin [7
], single-agent rituximab [8
], CHOP + rituximab [9
], VAD (vincristine, doxorubicin and dexamethasone) ± chlorambucil [10
], and CHOP followed by DHAP (dexamethasone, cisplatin and cytarabine) [11
], but none has shown clear superiority over the other with reported overall response rates (ORR) ranging from 30% to 90% and complete remission (CR) rates ranging from 10% to 90%. No regimen has consistently been proven to be curative and there were no major differences in the overall survival in many of these studies [5
12
]. Recently, Romaguera et al. [13
] presented their findings on 25 elderly patients who were treated with HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone), alternating every 3 weeks with high doses of methotrexate and cytarabine. They had an ORR of 92%, CR rates of 68% and median failure-free survival of 15 months after 17 months of follow-up.
Two recent studies examined the role of immunotherapy in the treatment of MCL. The German Low Grade Lymphoma Study Group treated patients with relapsed MCL using rituximab, fludarabine, cyclophosphamide and mitoxantrone (R-FCM). They found that patients in the R-FCM arm had higher remission rates than FCM alone (62% versus 43%) [14]. Zelenetz et al. [15
] enrolled patients with untreated MCL to sequential therapy with iodine I131 tositumomab (75 cGy) followed 1316 weeks later by CHOP chemotherapy for six cycles. The ORR to induction with radioimmunotherapy was 83%: CR 50%; partial response (PR) 33%.
Since conventional chemotherapy does not offer cure in most patients with MCL, high-dose chemotherapy followed by hematopoietic stem cell transplant (HSCT) has been looked at in an effort to improve survival rates. Although high-dose chemotherapy followed by autologous HSCT improves overall survival, reports suggest that this approach might not cure this disease [16]. There are a number of reports that have shown prolonged CRs with allogeneic HSCT even in cases of relapse after autologous HSCT [17
19
].
In the absence of randomized clinical trials, the exact role of HSCT in the treatment of MCL remains unclear. Also it is not known which type of transplantation represents the better therapy for patients with MCL. Hence we decided to study the clinical course of the disease in patients who received autologous and allogeneic HSCT for MCL, to determine whether the transplant modality had any effect on the clinical outcome of the patients.
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Patients and methods |
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Primary end points considered were response at day 100, mortality at day 100, relapse rate, event-free survival (EFS) and overall survival (OS). Response at day 100 was classified into CR, PR and no response or progressive disease. Disease-free survival (DFS) was defined as survival without evidence of worsening disease. For analyses of DFS, relapses or deaths from any cause were considered as events. For analyses of overall survival, events were deaths from any cause.
We were also interested in estimating the impact of prior therapy with HyperCVAD and high dose methotrexate and cytarabine ± rituximab on outcomes following transplantation. Hence we performed a subgroup analysis of patients who were transplanted after 2000 in order to use non-HyperCVAD cases from a comparable time period. This time frame was chosen in order to ensure that the two groups were comparable in all aspects except therapy with HyperCVAD.
The Wilcoxon rank-sum test and 2-test were used as appropriate to compare patient, disease and transplant characteristics between autologous and allogeneic transplant recipients. The cumulative incidence estimator was used to estimate the relapse rate and the KaplanMeier method was used to estimate the EFS and OS distribution. The log-rank test was to compare time-to-event variables.
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Results |
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Outcomes
The median follow-up of surviving patients is 33 months (range 3121). There was no statistically significant difference in the CR rate between patients receiving autologous and allogeneic transplants (73% versus 62%) (Table 2). Three deaths occurred in the first 100 days after transplant among recipients of allogeneic transplants (19%) compared with no deaths among those receiving autologous transplants (P <0.01). The causes of death among these patients were: acute respiratory distress syndrome, septic shock and Aspergillus infection. The estimated 5-year relapse rate was 21% among patients receiving an allogeneic transplant compared with 56% for those receiving an autologous transplant (P=0.11) (Figure 1). The estimated 5-year EFS was 44% for allogeneic transplants and 39% for autologous transplants (P=0.85) (Figure 2). The estimated 5-year OS was 49% for allogeneic transplants and 47% for autologous transplants (P=0.51) (Figure 3).
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Discussion |
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Our present study compared autologous and allogeneic HSCT for the treatment of MCL. We performed a univariate analysis to compare the two groups, and evaluate if the differences seen could be attributed to differences in patient or disease characteristics. We found that CR rate at day 100, 5-year estimated OS and 5-year estimated EFS were not significantly different amongst patients receiving autologous and allogeneic HSCT (73%, 47% and 39% versus 62%, 49% and 44%, respectively). These findings are similar to those seen in similar studies of other hematological malignancies like multiple myeloma, Hodgkin's disease and acute myeloid leukemia [2123
].
The estimated 5-year relapse rate was 21% among patients receiving an allogeneic transplant, compared with 56% for those receiving an autologous transplant (P=0.11). We feel that our study may have been underpowered to detect a difference between the two groups. In a similar study comparing autologous and allogeneic transplantation in patients with lymphoblastic lymphoma, Levine et al. [24] found that among patients who survived in remission for 6 months following HSCT, patients with autologous HSCT were more likely to suffer a subsequent relapse than patients who received allogeneic transplants, leading to a statistically significant difference in the cumulative incidence of relapse by 1 year after transplantation. The reasons for the lower risk of relapse are unclear but may involve a graft-versus-lymphoma effect. This could be similar to the graft-versus-leukemia effect that has clearly been demonstrated [25
, 26
]. Another possible explanation of the lower incidence of relapse is that re-infusion of autologous stem cells contaminated with tumor cells contributed to the higher relapse rate in the autologous HSCT group. This was borne out in a recent study in which patients who received unpurged autografts had a two-fold greater relapse risk than the recipients of purged autografts [27
].
Patients receiving allogeneic HSCT had a significantly higher early mortality compared with patients receiving autologous HSCT (19% versus 0%; P <0.01). The reported causes of death were acute respiratory distress syndrome, septic shock and Aspergillus infection. One of the reasons for this increased mortality may be that the receipients of allogeneic HSCT were more likely to receive radiation-containing conditioning regimens (94% versus 9%). It is possible that this contributed to increased organ toxicity and/or slower engraftment, leading to an overall increase in immediate transplant-related mortality. A similar phenomenon of increased transplant-related mortality has been reported in other studies comparing autologous and allogeneic transplantations for other hematological malignancies as well [2123
]. Khouri et al. [28
] performed a study on 18 patients in order to determine the efficacy of non-ablative allogeneic stem-cell transplantation in patients with relapsed MCL. They found a complete donor cell engraftment and no evidence of acute graft-versus-host disease or transplant-related deaths at 100 days. In their study, 17 out of the 18 patients achieved CR. This suggests that, selection bias notwithstanding, non-ablative allogeneic transplantation is a potentially effective strategy for patients with MCL.
An interesting and potentially important finding in our study was the absence of relapses or other adverse events amongst patients receiving HSCT after chemotherapy with HyperCVAD. Although the number of patients in our series was small and the follow-up short, our results confirm the findings of Khouri et al. [29], who treated 33 patients with aggressive MCL with HyperCVAD alternating with high-dose methotrexate and cytarabine for four cycles and then consolidated them with HSCT. They achieved a CR in all patients undergoing a transplant. At a median follow-up of 49 months, their estimated 5-year OS and DFS were 77% and 43%, respectively.
Our findings, like those from previous similar studies, suggest that the choice between allogeneic versus autologous stem cells does not affect the overall transplantation outcome. However, we did find almost 40% 5-year estimated EFS (44% and 39% for allogeneic and autologous transplants, respectively) and almost 50% 5-year estimated OS (49% and 47% for allogeneic and autologous transplants, respectively) in patients with MCL, regardless of the type of transplant. The pattern of treatment failure between autologous and allogeneic HSCT differs and may help in the design of future strategies. Because most patients lack an available allogeneic donor, new strategies to improve the outcome of autologous transplantation are needed. The lack of an obvious plateau in relapses after autologous transplantation indicates that late disease control is a major problem. Incorporation of current or future monoclonal antibody therapies, perhaps as post-transplantation consolidation, may be of value for these patients. Whichever source of hematopoietic stem cells is selected, greater cytoreduction before the transplant with an effective regimen such as HyperCVAD + rituximab may optimize results.
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Acknowledgements |
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Received for publication November 4, 2004. Accepted for publication November 9, 2004.
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References |
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