Annals of Oncology Advance Access originally published online on March 17, 2008
Annals of Oncology 2008 19(7):1327-1330; doi:10.1093/annonc/mdn045
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hematologic malignancies |
Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard therapies
1 Center for Lymphoma and Myeloma, Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College and New York Presbyterian Hospital
2 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College
3 Division of Biostatistics and Epidemiology, Department of Public Health, Weill Cornell Medical College and New York Presbyterian Hospital, New York, USA
* Correspondence to: Dr J. P. Leonard, Starr Building Room 340, Weill Cornell Medical College and New York Presbyterian Hospital, 520 East 70th Street, New York, NY 10021, USA. Tel: +1-212-746-2932; Fax: +1-212-746-3844; E-mail: jpleonar{at}med.cornell.edu
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Abstract |
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Background: Reported median overall survival (OS) in patients with mantle cell lymphoma (MCL) has been reported to be just 3–4 years. As a consequence, first-line treatment has become more aggressive. Single-center studies with R-Hyper-CVAD and/or autologous stem-cell transplant (ASCT) have produced 3-year OS rates >80%, prompting many to adopt their use. We evaluated outcomes from a single-center cohort managed in a more traditional fashion.
Methods: We identified patients with MCL evaluated at Weill Cornell Medical Center since 1997, and included those with known date of diagnosis. An online social security database was used to verify survival.
Results: We identified 181 patients with MCL, and date of diagnosis could be determined in 111. Three-year OS from diagnosis was 86% [95% confidence interval (CI) 78% to 92%]. Median OS was 7.1 years (95% CI 63–98 months). Adequate information on therapy was available for 75 patients. Only five were treated upfront with (R)-Hyper-CVAD or ASCT while an additional four patients received one of these regimens subsequently. Treatment type had no significant effect on OS.
Conclusion: Outcomes with standard approaches can yield similar survival to that achieved with more intensive approaches. Biases may account for the perceived superiority of aggressive strategies.
Key words: chemotherapy, hyper-CVAD, mantle cell lymphoma, stem-cell transplant
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introduction |
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Shortly after the inclusion of mantle cell lymphoma (MCL) in the 1994 revised European-American classification of lymphoid neoplasms, several groups, reported on their experience with this new entity [1–6]. It became recognized that MCL had the unfortunate characteristic of rapid progression, similar to aggressive lymphomas, and successive relapses (i.e. incurability) as observed in many indolent lymphomas. The median overall survival (OS) cited was in the range of 3–4 years. As a consequence, physicians had the task of selecting an optimal therapeutic approach. This undertaking resulted, to some degree, in a dichotomy of philosophies. Some centers pursued less aggressive treatments, accepting that patients would not be cured but also would be less likely to suffer treatment-related toxicity. Others pursued more aggressive treatments such as fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD) and/or high-dose chemotherapy with autologous stem-cell transplant (ASCT) in first remission. Recently published experiences with these intensive therapies have produced impressive results. In 2005, Romaguera et al. [7] published the results of a single-center phase II trial employing rituximab plus Hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. Ninety-seven percent of patients responded with an 82% 3-year OS rate. Also in 2005, Ganti et al. [8] published their single-center experience with patients who underwent hematopoietic stem-cell transplantation for MCL. The 5-year OS of 80 patients who underwent ASCT was 47%. Despite these authors’ cautious interpretations of their results, several centers worldwide now consider aggressive therapies as standard of care. It is important to note, however, that intensive treatment strategies are only applicable to a subset of MCL patients, specifically those who are not excluded by age and comorbidities.
Given that there is no evidence that intensive treatment strategies are curative in MCL, we have typically treated patients at our center with a less aggressive, traditional approach. We hypothesized that the impressive treatment results reported in single-center cohorts treated in an intensive fashion might be due, at least in part, to selection and referral biases rather than true superiority. While intensive strategies are likely to improve progression-free survival, OS is the key primary end point. In this report, we analyze the outcomes of MCL patients seen at the Weill Cornell Medical Center, a group of patients potentially shaped by similar biases but treated in a more standard fashion.
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methods |
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patients
Upon local Institutional Review Board (IRB) approval, we used surgical pathology records to identify patients with a diagnosis of MCL evaluated at Weill Cornell Medical Center between 1997 and 2007. Standard diagnostic criteria were employed [1]. Patients were eligible if an initial date of diagnosis, defined as the date of the first diagnostic biopsy or the date of diagnosis in the medical record, could be identified. Hospital and clinical research charts were reviewed for identification of prognostic and treatment-related information. Date of death was derived from hospital records and verified using an online social security death index (SSDI) [9]. The SSDI may not include all persons. Potential reasons why someone might not appear in the index include the following: the death was not reported to the social security administration; the person did not participate in the social security program; a recent death may not be indexed yet and human error. The SSDI is widely employed in the medical literature for the purpose of assessment of vital status in various settings.
statistics
OS was defined as time from diagnosis to date of death from any cause. OS was estimated according to the Kaplan–Meier method. Univariate analysis of prognostic markers was performed by Cox regression analysis.
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results |
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patients
One hundred and eighty-one patients with MCL were identified in the pathology database. Forty-eight of these were consultations to our pathology department without available clinical information. Of the remaining 133, date of diagnosis could be identified in 111 subjects. This cohort was used to calculate OS. Median follow-up is 41 months. Specific information on therapy was available for 75 patients. Other prognostic data, such as the international prognostic index (IPI), could be identified in cohorts of varying size, and these numbers are reported where applicable.
patient characteristics
The characteristics of patients are summarized in Table 1. The median age at diagnosis was 63 years (range 37–88 years). The male-to-female ratio was 4:1. In the subset of patients with available clinical information, age was not different and the majority had advanced stage—90% were stage III or IV—and bone marrow involvement (75%). All patients with available information had a good performance status. About half had an IPI score of 3–5.
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treatment characteristics
Treatment details are summarized in Table 2. Of the 75 patients with available treatment-related information, 70% received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like or rituximab-CHOP (R-CHOP)-like first-line treatment. Only five patients received (R)-Hyper-CVAD and/or ASCT as part of first-line therapy. An additional four patients received one of these regimens as subsequent therapy. No patients received allogeneic stem-cell transplantation.
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overall survival
The median OS from diagnosis of all 111 patients was 85 months (95% CI 63–98 months). The OS rate at 3 years was 86% and at 5 years was 66% (Figure 1). Five patients were alive >10 years from diagnosis—one is alive at 15.4 years—despite never receiving Hyper-CVAD or ASCT. While age, lactate dehydrogenase (LDH) and IPI tended to negatively affect OS, the differences were not statistically significant [age > 60 years, hazard ratio (HR) 1.46, 95% CI 0.78–2.74], LDH (LDH > upper limit of normal (ULN), HR 2.29, 95% CI 0.83–6.33) or IPI (IPI < 2, HR 0.34, 95% CI 0.09–1.33). Bone marrow involvement did correlate with a worse OS but the CI was wide (HR 5.28, 95% CI 1.22–23.69). Comparison among those treated with aggressive therapy (i.e. Hyper-CVAD and/or ASCT) versus those treated with a more conservative approach demonstrated no significant effect on OS (HR 0.70, 95% CI 0.25–2.00) though the number of patients treated aggressively was small (n = 9). The difference in survival between those patients with available treatment data and those without was not different (HR 2.11, 95% CI 0.93–4.78).
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discussion |
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OS data from single-center studies employing intensive strategies in MCL have led some investigators and clinicians to adopt them as standard of care. Our data demonstrate that the median OS of MCL patients treated at a similar referral center but with more standard approaches are quite comparable. These findings provide strong data that question the perceived superiority of intensive strategies and indicate that adequately powered prospective multicenter clinical trials are necessary to clarify this issue.
One interpretation of our data and other recent studies is that the prognosis of patients with MCL has improved significantly over the past decade. Over that same period of time, rituximab has become nearly ubiquitous, bortezomib was licensed by the Food and Drug Administration for relapsed MCL and other agents such as thalidomide and temsirolimus have shown promise in clinical trials. A similar pattern has been seen in patients with follicular lymphoma [10, 11]. Our patient population has been treated over roughly the same time period as those cohorts recently reported with aggressive treatments. It is, therefore, difficult to attribute the outcomes of our group, relative to the intensive cohorts, solely to the availability of new agents.
Table 3 summarizes the outcomes from the Romaguera (R-Hyper-CVAD) and Ganti (high-dose chemotherapy and ASCT) series relative to our own. We recognize the hazards of comparisons across different studies with different patient populations, but it is important to put our findings in some general context. These two studies are useful benchmarks as they are the largest, modern single-center experiences available that describe results with the two most commonly employed intensive treatment strategies treated over a similar time period as our cohort. While larger series exist, they are multicenter and/or registry data that do not serve as a comparable population to our group. It is noteworthy that our OS data obtained with largely standard approaches are similar to those achieved with the intensive strategies, even when our analysis is confined to our subset who received standard, nonintensive treatment. The Romaguera study was a prospective, phase II study that, in terms of levels of evidence, is superior to our retrospective cohort design. Patients with a pure mantle zone pattern were excluded on the basis of limited evidence that those patients may have a more indolent disease course. However, these investigators also excluded patients with central nervous system involvement, human immunodeficiency virus, pregnancy or comorbid physical or mental illness precluding therapy while we report on all patients with an identifiable date of diagnosis. Finally, Romaguera and colleagues measured survival from date of treatment, whereas we measured OS from date of diagnosis, perhaps resulting in lead-time bias if patients in their study waited an extended time between diagnosis and treatment. The Ganti study was a retrospective cohort study, as in our report. While it was not explicitly stated, it appears that all patients who underwent transplant during the stated time were included in their study.
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Our study is also subject to the potential for selection bias. As a large referral center (as in the Romaguera and Ganti studies) there may have been referral bias. One-third of the patients in our cohort had previously been treated and were referred at the time of relapse, perhaps resulting in bias toward a group of patients who did not die during first-line therapy. Of the 133 patients who were treated at our center, the precise date of diagnosis could not be identified for 22. It is unknown whether this group had a better or worse prognosis than the cohort for whom a date of diagnosis could be identified. All patients, regardless of MCL variant, were included. In fact, our pathology department does not routinely report MCL variants other than blastoid/large cell. While the question of whether patients with mantle zone variant have a better prognosis is controversial, we cannot exclude that an unusual number of our cohort consisted of these patients. In addition to selection bias, information bias may also have influenced our results. Prognostic- and treatment-related data were available for a limited subset of the larger cohort, and we cannot rule out that these subsets did not differ in some way from the whole. Also, we defined OS as time from diagnosis to time of death from any cause while most treatment trials define OS from time of therapy. This lead-time bias must be considered when comparing our results to those of other groups reported here. Many of these sources of bias, however, are not unique to our study but in fact are common in all nonrandomized trials, including those of Romaguera and Ganti. Additionally, there are clear patient selection biases in all reports of intensive treatment strategies in MCL. While our report describes all patients at our center (identified by pathology), clearly there are patients seen at the other institutions who were not candidates for intensive approaches due to age or comorbidities. These less favorable patients would be excluded from such reports as they would not be candidates for studies of aggressive therapy, or perhaps would not be referred to the institution at all. This situation would result in biases that would make intensive treatment trials appear more effective.
Unfortunately, there have been relatively few randomized studies in MCL. In the German Low-Grade Lymphoma Study Group phase III trial comparing R-CHOP to CHOP in patients with MCL, the 2-year OS rate in both groups was 
75% [12]. In a phase III trial of the European MCL network that compared ASCT with maintenance with interferon-
, the 3-year OS in the transplant arm was 83% while that in the maintenance arm was 77%, with no statistically significant difference between the two (P = 0.18).
Several decades ago in diffuse large cell lymphoma, on the basis of impressive single-center phase II trials, many considered the aggressive treatments ProMACE-Cytabom and m-BACOD to be standard of care. Ultimately, what some considered to be an unethical randomized trial failed to demonstrate their superiority of over CHOP. This remained the standard of care until 2002 when the addition of rituximab was shown to produce superior results by other randomized trials [13, 14]. Single-center studies, including our own, are prone to considerable bias, only some of which is identifiable or correctable. Such reports can only go so far in arguing for or against the superiority of one treatment versus another and should not be accepted as convincing with respect to changing standard of care, particularly when there may be marked differences in toxicity with the different options. Our data strongly argue for the importance of adequately powered, multicenter randomized trials with OS as a primary end point in order to define the optimal therapy for MCL.
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National Cancer Institute of Canada to P.M.; Lymphoma Research Foundation and the Lymphoma Foundation to J.P.L.
Received for publication November 28, 2007. Revision received January 25, 2008. Accepted for publication January 31, 2008.
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References |
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