We retrospectively analyzed 44 patients undergoing first-line treatment for mantle cell lymphoma with R-HyperCVAD, with or without rituximab (R) maintenance or auto-SCT. The primary study end point was PFS; secondary end point was overall survival.
Median follow up for all patients was 3.3 years. Median age was 54 years, and 95% (n=42) were stage III or IV at diagnosis. In all, 17 patients underwent consolidative auto-SCT and 12 patients received R maintenance. The overall response rate was 95%, with 91% achieving complete response (CR). Median PFS for all patients was 3.5 years. Median PFS was 2.3 years for patients treated with R-HyperCVAD alone vs 3.9 years (P=0.02) with R-HyperCVAD+ R maintenance and 4.5 years (P=0.01) with R-HyperCVAD+ auto-SCT. For patients who did not achieve CR at interim staging, PFS for R-HyperCVAD alone was 1.4 years vs not reached for R-HyperCVAD+ consolidation (either R maintenance or auto-SCT) (P=0.02). PFS for patients with CR at interim staging was 3.3 years vs not reached (P=0.04) after consolidation. Our data suggest potential improvement in PFS when R-HyperCVAD is consolidated with either R maintenance or auto-SCT. This benefit appears particularly significant in those patients who do not achieve CR at interim restaging.
Mantle cell lymphoma (MCL) comprises about 6–8% of newly diagnosed non-Hodgkin lymphoma.1 It is generally considered an incurable disease with conventional treatments. Historically, median overall survival (OS) has been reported to be 3–4 years with standard lymphoma regimens.2
Although high response rates can be observed with CHOP plus rituximab (R), the median PFS is unsatisfactory, ranging from 16 to 20 months.3, 4 Several strategies have been employed in a number of phase II studies, attempting to improve median PFS with either dose intensification or high-dose chemotherapy consolidation.5, 6, 7, 8, 9, 10 Favorable results have been reported for the R-HyperCVAD regimen alternating with R-high-dose MTX/cytarabine. At 10-year follow up, the median time-to-failure for all patients was 4.6 years, with a time-to-failure of 5.9 years in patients aged ⩽65. However, a plateau had not been observed and the median OS had not been reached at the time of publication.11 Outcomes for patients >65 were compromised by treatment-related toxicities. The Nordic study group treated patients with a dose-intensified CHOP-like regimen (maxi-CHOP) alternating with R-high-dose cytarabine and followed by consolidation high-dose chemotherapy and auto-SCT. The data suggested the possibility of cure for untreated MCL patients because there were no reported failures after 5 years in patients aged ⩽65. Although the 6-year EFS was reported to be 56%, these results are limited by the rather short median follow up of 3.4 years.12
R maintenance has previously been shown to confer clinical benefit in several non-Hodgkin lymphoma subtypes.13, 14 Kahl et al. reported the results of a small pilot study in 22 patients, utilizing a modified R-HyperCVAD regimen without MTX and cytarabine. The addition of R maintenance produced a median PFS of 37 months, with most relapses noted upon discontinuation of R maintenance.15 Another randomized trial conducted by the German Low Grade Lymphoma Study Group compared 1 year of R maintenance with observation in patients with relapsed follicular lymphoma and MCL.16 The results suggested an added benefit for R maintenance in the treatment of MCL. A recent retrospective analysis of data from two German lymphoma groups indicated that over the past 30 years the median OS for patients with MCL almost doubled and currently is close to 5 years.17 Contributing factors to the improved OS may be the addition of R, dose-intensified chemotherapy regimen, incorporation of high-dose cytarabine and high-dose chemotherapy consolidation. However, the lack of comparative randomized trials in the frontline setting and the variety of reported treatment approaches allow for considerable debate regarding the optimal management of advanced MCL.
In this article we report the results of a retrospective study of 44 consecutive, unselected patients with advanced MCL who were initially treated with R-HyperCVAD. Patients either received no further consolidation, R maintenance or high-dose chemotherapy with auto-SCT according to the treating physician's choice.
Patients and methods
Study design and patients
This retrospective analysis was conducted using clinical data pertaining to treatment modalities, efficacy and disease course collected from consecutive, unselected patients treated at the University of Pennsylvania. All new patient visits from 2005 to 2009 as well as follow-up visits in 2005 were searched. All patients meeting the following criteria were included: (i) pathologic diagnosis of MCL, (ii) treatment with R plus HyperCVAD alternating with high-dose MTX and cytarabine (R-HyperCVAD). As our electronic database started in 2005, all new patient visits from 2005 to 2009 as well as follow-up visits in 2005 were searched for patients fitting these criteria. This was done to ensure (a) long enough follow up as well as (b) availability of electronic clinical data. Forty-four patients were identified who received treatment with R-HyperCVAD between 3 January 1999 and 15 October 2009. The last follow up available for this analysis was obtained on 1 March 2011, and the median follow up was 3.3 years. The Institutional Review Board at the University of Pennsylvania reviewed this study. Recommendations concerning data management and protection of human subjects were followed.
R-HyperCVAD (cycle A) was given to inpatients on a 21-day cycle with R (375 mg/m2) on day 1, followed by CY (300 mg/m2) per dose administered every 12 h for six doses on days 2,3 and 4. Adriamycin (50 mg/m2) (as a bolus) and VCR (2 mg) were given immediately after the last dose of CY on day 3. Dexamethasone (40 mg) was given on days 1–4. Patients with evidence of peripheral-blood involvement, as determined by flow cytometric analysis at the time of initial presentation, may have had their first dose of R delayed or omitted at the discretion of the clinician if there was concern for risk of tumor-lysis syndrome or cytokine-release syndrome.
Cycle B was a 21-day cycle administered to inpatients and consisted of R (375 mg/m2) on day 1, followed by MTX (1000 mg/m2) IV over 24 h. Cytarabine was administered at a dose of 3 g/m2 per dose over 2 h every 12 h for four doses on days 3 and 4 of the cycle. The dose of cytarabine was reduced to 1 g/m2 per dose in patients >60 years and in patients with a serum creatinine level >1.5 mg/dL. Patients alternated cycles A and B for up to a total of eight cycles. All patients received growth factor and antimicrobial prophylaxis through the course of therapy. For patients considered for auto-SCT, PBSC harvest was initiated after the fifth cycle of chemotherapy.
R maintenance was given as 4 weekly infusions of 375 mg/m2, repeated every 6 months over a course of 2 years.18
Patients undergoing high-dose chemotherapy with auto-SCT (n=17) were conditioned either with CY and TBI (CY/TBI) (n=12) or the BEAM (BCNN, etoposide, cytarabine, melphalan) regimen (n=5).
Patients who received at least one cycle of R-HyperCVAD were assessed. Response or disease progression was evaluated according to the International Working Group recommendations.19 Staging positron emission tomography (PET) imaging was performed on all patients, and fluorodeoxyglucose (FDG) avidity was included in interim staging and response assessment unless the disease was not FDG avid on initial staging (n=7). Response was assessed at interim (fourth or sixth cycle) and upon completion of therapy. PFS was defined at the time from the first dose of chemotherapy to disease progression or death. OS was measured from initiation of therapy. Patients with either progressive disease or progression within 6 months (n=1) were excluded from the comparative analysis between R-HyperCVAD alone and R-HyperCVAD, followed by consolidation with either R maintenance or auto-SCT.
Event-related data (PFS and OS) were estimated using the Kaplan-Meier method, and comparison of outcomes between the three subgroups, that is, R-HyperCVAD alone, R-HyperCVAD followed by R maintenance or R-HyperCVAD followed by auto-SCT, were made using the log-rank test (Mantle-Cox). χ2-test was used to determine differences of baseline characteristics between the three groups. For all statistical analysis, the significance level was set at P<0.05, in two-sided tests. Statistical analysis was performed with the GraphPAD Prism program (La Jolla, San Diego, CA, USA)
A total of forty-four consecutive, unselected patients with MCL treated with R-HyperCVAD were included in this study. Patient demographics and baseline characteristics are detailed in Table 1.
The median follow up for all patients was 3.3 years (range: 1–12). The median age at time of diagnosis was 54 years and 42/44 (95%) had advanced (Stage III or IV) disease. Twenty-nine patients underwent further consolidation upon completion of the R-HyperCVAD treatment: twelve patients continued with R maintenance, whereas seventeen were consolidated with auto-SCT (Table 1). Comparing baseline characteristics between the three groups (that is, R-HyperCVAD alone vs R-HyperCVAD+ R maintenance vs RH-CVAD+ auto-SCT), the only significant difference noted was in age between the R-HyperCVAD alone group and R-HyperCVAD+ R maintenance (58 vs 50 years, P=0.02). Otherwise, there were no statistical differences in terms of stage, ECOG PS, LDH, WBC, BM or GI involvement, bulky disease or blastoid variant at baseline.
Six patients had received prior treatment: two patients had received up to three cycles of CHOP, two patients had been treated with single agent R, one patient had been previously treated with R, CY and prednisone, and one patient had been on hydrea. A total of 32 out of 44 patients (73%) completed all eight cycles of R-HyperCVAD. Two patients had to be changed to R-CHOP because of inability to tolerate R-HyperCVAD (both of whom subsequently were consolidated with auto-SCT). Chemotherapy was dose-reduced in 12 patients, and a total of 30 patients experienced time delays during their course of treatment. The most notable toxicity was neutropenic fever in 28 patients; the most significant noninfectious adverse events included pleural effusion, pneumonitis or pulmonary fibrosis (n=4), neuropathy (n=1) and allergic reaction to R (n=1). Seven patients underwent local radiation before or during treatment.
A total of five patients failed to mobilize stem cells after R-HyperCVAD, two of whom were subsequently consolidated with R-maintenance.
Responses and PFS
Response to R-HyperCVAD was evaluated on all 44 patients. The overall response rate was 95%, with 91% achieving complete response (CR).
Median PFS for all patients was 3.5 years, which is comparable to previous studies (Figure 1). Median PFS for patients treated with R-HyperCVAD alone was 2.3 years vs 3.9 years for R-HyperCVAD+ R maintenance (P=0.02, Hazard ratio (HR): 3.3, 95% confidence interval (CI): 1.2–8.9) and 4.5 years for R-HyperCVAD+ auto-SCT (P=0.01, HR: 3.4, 95% CI: 1.3–8.9). At 2 and 5 years, PFS for R-HyperCVAD alone, R-HyperCVAD+ R maintenance and R-HyperCVAD+ auto-SCT were 64%, 88% and 70%, and 0%, 48% and 46%, respectively. Notably, only 1 of 10 patients treated with R-HyperCVAD+ auto-SCT relapsed after 2 years, with a median follow up of 3.3 years for these patients (Figure 2).
There was no statistically significant difference between the two consolidative approaches (that is, R-HyperCVAD+ R maintenance or R-HyperCVAD+ auto-SCT). Response at interim was a significant prognostic factor. Median PFS for patients without CR at interim was 2 years vs 3.9 years for those with CR (P=0.03, HR: 2.8, 95% CI: 1.1–7.1) (Figure 3).
Among patients who did not achieve a CR at interim staging, PFS for R-HyperCVAD alone was 1.4 years vs not reached for R-HyperCVAD+consolidation (either R maintenance or auto-SCT) (P=0.02, HR: 5.4, 95% CI: 1.3–21.9) (Figure 4). A less pronounced but still significant benefit for further consolidation was observed in patients with CR at interim staging with PFS 3.3 years vs not reached (P=0.04, HR: 4.9 95% CI: 1.1–22.3) (Figure 5). Although there was no statistically significant benefit in terms of OS for both consolidative approaches, patients may have gained some advantage from consolidation (median OS 4.1 years vs not reached, P=0.3).
Mantle cell lymphoma remains a conundrum for the treating clinician. Without randomized clinical trials for reference, clinical decisions are based on patient and disease characteristics, as well as the limitations of available therapies. Previously published work indicates that standard-dose therapies are inadequate. Proposed means for improving outcome include increased dose intensity, the addition of agents such as cytarabine and R, and high-dose consolidations. In a retrospective survey such as ours, clinicians used three treatment approaches, based on a variety of clinical factors. Therefore, there are limitations to drawing definite conclusions. However, beyond a significant difference in age between R-HyperCVAD alone group and R-HyperCVAD+R maintenance group, there were no detectable differences in patient characteristics between the three approaches for a number of previously described risk factors. Obviously, given the relatively small numbers within each subgroup and lack of available data in some patients, we cannot exclude that the three subgroups are unbalanced.
Our data appear to demonstrate a clear and striking advantage in terms of PFS for the use of consolidation with either R maintenance or auto-SCT in MCL patients treated with R-HyperCVAD.
We are limited by the size of our retrospective analysis to compare the benefits of each approach in relation to the interim staging response. However, pooling outcomes for both consolidative approaches documents a benefit for further consolidation in those patients who achieved a CR at interim. There is an even more impressive improvement of otherwise limited PFS with consolidation in those patients who did not achieve a CR at interim. The substantial improvement in PFS for those patients with residual disease at interim, when further consolidated after R-HyperCVAD with either R or auto-SCT, further suggested an improved OS. This OS benefit was not statistically significant.
Our results emphasize the potential role for consolidation of patients with MCL treated with R-HyperCVAD with either R maintenance or auto-SCT. Although these results appear not to be restricted to those patients with residual disease at interim, they are more pronounced in this particular subgroup.
In a retrospective analysis such as ours, we cannot control for the underlying biases (both positive and negative) of the treating physicians choices. With relatively small numbers within each subgroup there is also a lack of statistical power to detect imbalances for baseline characteristics and prognostic factors. Although the R-HyperCVAD regimen is the preferred treatment for any fit patient with MCL and age <65 years at the University of Pennsylvania, there is no consensus within the group of treating physicians regarding the role of further consolidation. In most cases, the treatment plan was a priori formulated on the basis of each physician's own biases. Thus, the improvement in PFS in those patients with residual disease at interim particularly warrants further investigation and validation of consolidative approaches after R-HyperCVAD.
Given the limited number of patients, we were unable to detect any differences between R maintenance and auto-SCT as a consolidative approach. This is important, as the recent reports from the Nordic study group have been interpreted as a validation of the auto-SCT consolidation approach.12 It is, however, worth noting that a less appreciated detail of the Nordic study group has been the continued treatment of minimal residual disease with R. To our knowledge, there is only one report of R maintenance in MCL in the frontline setting; that trial design incorporated a dose-reduced version of R-HyperCVAD.15 Ours is the first cohort reported with R maintenance following a full-dose R-HyperCVAD treatment plan. As such, our results are intriguing and argue for a possible role of R maintenance in the management of patients with MCL. In the past, the randomized study of R maintenance in MCL conducted by the Swiss Group of Clinical Cancer Research had questioned the role of R maintenance in MCL.20 However, this study was investigating R maintenance after induction therapy with single agent R. As such, our data studies a different scenario, where R maintenance is given after intensive chemotherapy, presumably in a minimal residual disease state, as well as a different maintenance regimen (8 doses over 8 months in the Swiss Group of Clinical Cancer Research study vs 16 doses over 24 months). Others already have shown a particular benefit for R maintenance in the setting of minimal residual disease.14 Indeed, the particular striking benefit in our data for patients with residual disease interim seems to highlight the role for further consolidation in a presumably minimal residual disease state after intensive chemotherapy. Our study suggests that prospective investigation into consolidative approaches after R-HyperCVAD is warranted. Furthermore, these results suggest a role for a response-adapted approach that may allow for tailored treatment intensification with either R maintenance or auto-SCT.
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TA is a Special Fellow in Clinical Research of the Leukemia and Lymphoma Society
The authors declare no conflict of interest.
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Ahmadi, T., McQuade, J., Porter, D. et al. Potential prolongation of PFS in mantle cell lymphoma after R-HyperCVAD: auto-SCT consolidation or rituximab maintenance. Bone Marrow Transplant 47, 1082–1086 (2012). https://doi.org/10.1038/bmt.2011.218
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