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Keywords:

  • mantle cell lymphoma;
  • relapse;
  • allogeneic stem cell transplantation;
  • autologous stem cell transplantation;
  • rituximab

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. REFERENCES

BACKGROUND:

Autologous stem cell transplantation (autoSCT) has improved the outcome of patients with mantle cell lymphoma (MCL) considerably. However, little is known about the patterns and outcome of MCL recurrence after autoSCT.

METHODS:

The authors conducted a retrospective study of 118 patients with MCL who underwent autoSCT from August 1992 to August 2008 at 3 different referral centers in Germany.

RESULTS:

Fifty-two relapses occurred for a cumulative incidence of 46% after 5 years. Only 3 patients relapsed after 5 years (at 90 months, 91 months, and 171 months) after undergoing autoSCT. A Cox regression analysis of the incidence of relapse identified not receiving rituximab before autoSCT and undergoing salvage autoSCT as predictive factors for relapse, whereas cytosine arabinoside intensification; a total body irradiation-based, high-dose regimen; patient age; and year of transplantation had no influence. The median overall survival (OS) after relapse was 23 months. Twenty patients (39%) underwent allogeneic stem cell transplantation (alloSCT) for relapse, and 11 of those patients remained in ongoing complete remission at the time of the current report. It is noteworthy that there were 4 long-term survivors who lived for >5 years after relapse even without undergoing alloSCT. A Cox regression analysis of OS after relapse revealed that the response duration after autoSCT was an adverse predictor of OS, whereas alloSCT was associated with a significantly longer OS after relapse.

CONCLUSIONS:

The current results indicated that autoSCT was capable of inducing long-term remission up to 16 years after treatment, but the outcome of patients with MCL who relapsed after autoSCT was poor, especially if their response duration after autoSCT was short. However, for a subset of patients with relapsed MCL, alloSCT may offer the possibility of durable survival, and individual patients can enjoy long-term survival after relapse even without undergoing alloSCT. Cancer 2011. © 2010 American Cancer Society.

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma that is characterized by early dissemination, an unfavorable clinical course, and a median survival <3 years when patients receive conventional chemotherapy.1-4 Evidence is accumulating that high-dose chemotherapy followed by autologous stem cell transplantation (autoSCT) improves patient outcomes, particularly if it is used as part of first-line treatment.5-12 Dreyling et al demonstrated that, after initial chemotherapy with combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP), patients with MCL who were assigned randomly to undergo autoSCT had a significantly better progression-free survival (PFS) than patients who were assigned to receive interferon maintenance.13

Although the efficacy of autoSCT seems to be improved further with the addition of rituximab, and although long-term disease control may be possible in a substantial proportion of patients who undergo autoSCT as part of first-line treatment,12, 14, 15 relapse remains the main cause of treatment failure. Despite a better understanding of prognostic factors for relapse after autoSCT, few studies have addressed salvage treatment strategies and the fate of patients who develop disease recurrence after undergoing autoSCT for MCL. Therefore, we sought to analyze the patterns and outcomes of relapse in patients who underwent autoSCT as consolidation for first-line or salvage treatment of MCL before and after the advent of rituximab. We performed a retrospective study on a large sample of patients who received autografts for MCL in 3 large referral centers between 1992 and 2008. Our primary objective was to assess the outcome after relapse. Secondary objectives were to identify patterns of relapse, risk factors for relapse, and treatment variables that can predict survival after relapse.

The results suggest that the prognosis for patients with recurrent MCL after autoSCT is dismal, particularly if the disease recurs early. However, the prognosis for these patients may improve remarkably with a salvage strategy that includes allogeneic stem cell transplantation (alloSCT).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. REFERENCES

Patients

Eligible for this study were all patients who received high-dose therapy and also underwent autoSCT for MCL from August 1992 to August 2008 on consecutive protocols that were active at the University of Heidelberg or at the University of Kiel and the Asklepios Clinic St. Georg in Hamburg. Patients were followed and relapses were identified retrospectively.

Details of the eligibility criteria and the design of the original protocols have been published previously.5, 9, 14, 16 In brief, at all 3 institutions, consecutive patients who had a diagnosis of stage II, III, or IV MCL were included if they were between ages 18 years and 75 years, had an adequate performance status (Karnofsky score ≥80%), and had adequate organ function. Patients who underwent either upfront autoSCT or salvage autoSCT were included in this study. Diagnoses were made originally either by a member of the Hematopathology Reference Panel of the German Lymphoma Study Group or by a senior hematopathologist at the University of Heidelberg. All histopathologic subtypes, including the blastoid variant, were eligible. The Mantle Cell Lymphoma International Prognostic Index (MIPI) could not be used in the current study, because data on performance status and lactate dehydrogenase were not available for all patients.

The pretransplantation therapies and transplantation procedures that patients underwent have been described previously.5, 14, 17 In brief, pretransplantation therapy comprised induction with CHOP followed by combined dexamethasone, carmustine, etoposide, cytosine arabinoside (ara-C), and melphalan (Dexa-BEAM); combined dexamethasone, high-dose ara-C, and cisplatin (DHAP); or combined high-dose ara-C, and mitoxantrone (HAM) for stem cell mobilization and further debulking. Fourty-two patients (35%) had stem cells collected during the CHOP phase and proceeded to autoSCT without additional intensification. Twelve patients (Heidelberg, n = 2; Kiel/Hamburg, n = 10) were treated on protocols using immunomagnetic cluster of differentiation 34 (CD34)-positive selection (Isolex300 Magnetic Cell Separator; Baxter Healthcare Corp., Santa Ana, Calif) for ex-vivo B-cell depletion of the autografts.16

Myeloablative therapy consisted of total body irradiation (TBI) and high-dose cyclophosphamide. TBI was given in fractionated doses twice daily on 4 consecutive days for a total of 14.4 Gy (Heidelberg) or on 3 consecutive days for a total of 12 Gy (Kiel/Hamburg); and cyclophosphamide was infused on the days after TBI at total a dose of 200 mg/kg (Heidelberg) or 120 mg/kg (Kiel/Hamburg). Patients who had received previous radiotherapy received BEAM (Heidelberg: carmustine 300 mg/m2, etoposide 800 mg/ m2, cytarabine 1600 mg/m2, and melphalan 140 mg/ m2) or busulfan/cyclophosphamide (Kiel: busulfan 1 mg/kg of body weight 4 times daily for 4 days followed by cyclophosphamide 60 mg/kg for 2 days). After July 1997, preirradiated patients in Kiel also received BEAM. In Heidelberg, the TBI and cyclophosphamide combination was replaced in December 1999 by BEAM as standard myeloablative regimen also for nonpreirradiated patients. Seventy-seven patients (65%) had received rituximab before or during autoSCT, whereas the remaining patients were rituximab-naive either until they developed a relapse or until the end of follow-up.

Patients were followed every 3 months during the first 2 years after autoSCT, every 6 months between 3 years and 5 years after autoSCT, and every 12 months after 6 years. Six months after autoSCT, patients usually had a sonographic or computed tomography study, which was repeated once annually during the first 5 years after transplantation.

All protocols were approved by the responsible institutional review boards, and the patients provided written informed consent. One hundred eighteen consecutive patients who fulfilled the eligibility criteria for this study were analyzed retrospectively, including 65 patients from Heidelberg and 53 patients from Kiel/Hamburg. Patient characteristics at time of first diagnosis or transplantation are summarized in Table 1.

Table 1. Patient Characteristics and Details of Treatment Before Autologous Stem Cell Transplantation
Characteristic at Time of DiagnosisNo. of Patients (%)Details of Induction Treatment and First AutoSCTNo. of Patients (%)
  1. AutoSCT indicates autologous stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; Dexa-BEAM, dexamethasone, carmustine, etoposide, cytosine arabinoside, and melphalan; DHAP, dexamethasone, high-dose cytarabine, and cisplatin; HAM, high-dose cytarabine and mitoxantrone; BM, bone marrow; CR, complete response; PR, partial response; SD, stable disease; TBI, total body irradiation.

Sex Age at transplantation, y 
 Men91 (77) Median [range]57 [30-74]
 Women27 (23)  
Stage High-dose cytarabine treatment prior to autoSCT 
 I-II6 (5) CHOP only42 (35)
 III7 (6) Dexa-BEAM48 (40)
 IV105 (89) DHAP or HAM28 (24)
Proven BM involvement Timing of rituximab treatment 
 No24 (20) None41 (35)
 Yes93 (79) Before autoSCT only43 (36)
 Not known1 (1) During conditioning20 (17)
   Before autoSCT and during conditioning14 (12)
Blastoid histology16 (14)Upfront autoSCT 
   No23 (19)
   Yes95 (81)
Extranodal involvement Response before autoSCT 
 No46 (39) CR46 (39)
 Yes67 (57) PR66 (56)
 Not known5 (4) SD3 (3)
   Not known3 (3)
Percentage of KI-67 positive cells, n = 25 TBI-containing conditioning regimen 
 Median [range]30 [10-90] Yes73 (62)
   No45 (38)

Identification of Minimal Residual Disease Markers and Quantitative Reverse Transcriptase-Polymerase Chain Reaction Analysis

Centralized molecular analyses were performed by 1 of the authors (C.P.). Extraction of genomic DNA from peripheral blood and bone marrow, and t(11;14) and immunoglobulin heavy chain locus (IGH) gene multiplex polymerase chain reaction (PCR) analyses were performed as described elsewhere.18, 19 Gene scanning was done on an ABI PRISM 377 automated sequencer (Applied Biosystems, Foster City, Calif). Minimal residual disease (MRD) status was assigned at certain time points by investigating either blood, or bone marrow, or both if available. For parallel investigations of both blood and bone marrow, MRD was judged positive if at least 1 sample was positive. A molecular remission required MRD-negative results in 2 consecutive samples that were taken at different time points.

Statistical Analysis

The median follow-up was calculated using the reverse Kaplan-Meier method.20 Relapse incidence was calculated as the time from autoSCT to the endpoint of relapse and considering death without relapse as a competing risk. Overall survival (OS) after relapse was calculated as the time from relapse to death from any cause. Relapse incidence and OS were analyzed for the prognostic impact of pretransplantation and prerelapse variables in addition to postrelapse salvage treatment in univariate log-rank comparisons and multivariate Cox regression analyses. All statistical tests were 2-sided, and results with P values <.05 were considered statistically significant. Univariate calculations were done using MedCalc software (release 11.0; MedCalc Software bvba, Mariakerke, Belgium), and Cox regression analyses were performed with SPSS (release 11.5; SPSS, Inc., Chicago, Ill).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. REFERENCES

Relapse Incidence, Patterns of Relapse, and Overall Outcome

In total, 118 patients were included in the study, and only 1 patient died soon after autoSCT because of treatment-related complications. At a median follow-up of 6.3 years (range, 0.3–16.8 years), 52 relapses occurred in 118 at-risk patients. The 5-year relapse probability was 47% (Fig. 1A). Twelve patients (25%) developed recurrent disease within the first year after autoSCT, and 40 patients (75%) developed recurrent disease >1 year after autoSCT. However, only 3 patients relapsed >5 years (90 months, 91 months, and 171 months) after autoSCT. Relapses occurred at least at 1 initially involved site, and local or general lymph node progression was the predominant site of relapse. During later phases of relapse, additional sites were involved, including 2 patients who presented with a third nerve palsy and visual field defect, which was caused by meningeal disease (Table 2).

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Figure 1. The incidence of relapse in patients with mantle cell lymphoma is illustrated for (A) patients after autologous stem cell transplantation (autoSCT), (B) patients who underwent transplantation in first remission (dashed line) and after first remission (solid line), (C) patients who underwent upfront transplantation and either received rituximab before autoSCT (dashed line) or did not receive rituximab before autoSCT (solid line), and (D) patients who underwent salvage transplantation and either received rituximab before autoSCT (dashed line) or did not receive rituximab before autoSCT (solid line).

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Table 2. Patterns of Relapse After Autologous Stem Cell Transplantation
Pattern of RelapseNo. of Patients (%)
  1. BM indicates bond marrow; CNS, central nervous system.

Proven BM involvement33 (63)
Extranodal involvement25 (48)
Gut involvement9 (17)
New, previously uninvolved sites 
 Gut2 (4)
 CNS involvement2 (4)
 Orbital masses2 (4)
 Pharyngeal masses3 (6)
 Breast1 (2)
 Skin1 (2)

For all 118 patients, the 5-year PFS rate was 54% (95% confidence interval [CI], 45%-64%), and the 5-year OS rate was 75% (95% CI, 67%-85%) Four patients developed a secondary solid tumor, 1 patient developed a secondary acute myeloid leukemia and 1 patient developed myelodysplastic syndrome.

Prognostic Factors for Relapse After AutoSCT

Univariate analysis revealed that patients who underwent autoSCT during first-line treatment had a significantly lower relapse incidence than patients who underwent autoSCT as part of salvage treatment (P<.01; hazard ratio [HR], 0.26; 95% CI, 0.11-0.59) (Fig. 1B). Rituximab treatment before or during autoSCT was associated with a lower risk of relapse compared with no rituximab treatment. It is noteworthy that the benefit of rituximab treatment was restricted to patients who underwent autoSCT in first remission (P = .03; HR, 0.48; 95% CI, 0.24-0.95) (Fig. 1C), whereas patients who underwent salvage transplantation did not befit from rituximab treatment (HR, 1.33; 95% CI, 0.40-4.47) (Fig. 1D). A significant impact of timing (pretransplantation, peritransplantation, or both) and dose on the beneficial effect of rituximab on the risk of relapse after first-line autoSCT could not be demonstrated (Fig. 2). Treatment intensification before autoSCT with ara-C–containing regimens (HR, 0.60; 95% CI, 0.30-1.16), remission status at autoSCT (complete remission [CR] vs partial remission/stable disease [PR/SD]: HR, 0.80; 95%CI, 0.46-1.40), and TBI as a part of the conditioning regimen (HR, 0.58; 95% CI, 0.32-1.06) had no significant influence on relapse, even if assessed in the 95 patients who underwent first-line autoSCT only (ara-C: HR, 0.98; 95% CI, 0.45-2.17; TBI: HR, 0.82; 95% CI, 0.40-1.73; CR vs PR/SD: HR, 0.90; 95% CI, 0.47-1.73) (Fig. 3).

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Figure 2. This chart illustrates the impact of timing on rituximab administration before autologous stem cell transplantation. HR indicates hazard ratio; CI, confidence interval.

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Figure 3. The incidence of relapse is illustrated among patients with mantle cell lymphoma who (A) underwent autologous stem cell transplantation (autoSCT) in first remission and received an intensified cytosine arabinoside (ara-C)-containing salvage regimen before first autoSCT (solid line) compared with patients who received combined cyclophosphamide, vincristine, doxorubicin, and prednisone only (dashed line); (B) patients who received a total body irradiation-containing conditioning regimen (solid line) compared with patients who received combined carmustine, etoposide, ara-C, and melphalan (dashed line); and (C) patients who achieved complete remission (solid line) compared with patients who had a partial remission or stable disease before transplantation (dashed line).

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Cox regression analysis adjusting for rituximab exposure, ara-C intensification, line/timing of autoSCT, and TBI, conditioning in addition to the continuous variables calendar year of autoSCT and patient age, confirmed that rituximab treatment before autoSCT and upfront autoSCT predicted a lower risk of relapse (Table 3). The MIPI at diagnosis was available for too few patients to allow an informative analysis.

Table 3. Multivariate Analysis of Risk Factors for Relapse After Autologous Stem Cell Transplantation
 PHR95% CI for HR
Variable  LowerUpper
  1. CI indicates confidence interval; HR, hazard ratio; autoSCT, autologous stem cell transplantation; R, rituximab; ara-C, cytosine arabinoside; TBI, total body irradiation.

Upfront vs salvage autoSCT.030.440.210.90
R vs no R before autoSCT.010.230.080.70
Ara-C vs no ara-C before autoSCT.630.820.361.85
TBI vs no TBI.330.670.291.50
Age at time of autoSCT.840.990.961.03
Calendar year of autoSCT.111.140.971.35

Survival and Treatment After Relapse

At a median follow-up after relapse of 54 months (range, 3-140 months), 30 patients died, which translated into a median OS after relapse of 23 months (Fig. 4A). The cause of death was progressive disease in 18 patients, treatment-related mortality (TRM) because of alloSCT in 9 patients, TRM because of a second autoSCT in 1 patient, secondary acute myelocytic leukemia in 1 patient, and unknown in 1 patient.

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Figure 4. Overall survival after autologous stem cell transplantation (autoSCT) is illustrated (A) for all 52 patients who experienced a relapse, (B) for the patients who had a relapse-free survival <12 months after undergoing autoSCT (dashed line) versus >12 months (solid line), and (C) for the patients who either underwent allogeneic stem cell transplantation (alloSCT) (solid line) or did not undergo alloSCT (dashed line) after autoSCT failure.

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Treatment of relapse comprised a median of 2 additional lines of chemotherapy (range, 0-5 additional lines). The relapse regimens that were used were very heterogeneous and included aggressive combination therapies, such as DHAP, Dexa-BEAM, and combined fludarabine, cyclophosphamide, and mitoxantrone, as well as palliative regimens, such as bortezomib, gemcitabine, vindesine, or rituximab only. Most often, a fludarabine-based salvage regimen was used (n = 27; 52%). Four patients (8%) underwent a second autoSCT, and 20 patients (39%) underwent an alloSCT, which was performed with reduced-intensity conditioning in each individual patient. Of all 20 patients who received allografts, 8 patients died because of complications of the alloSCT, and 1 patient died because of relapse. Another patient relapsed and was brought into CR again with donor lymphocyte infusions and chemotherapy, whereas 10 patients remained alive in continuous CR after alloSCT at a median observation time after relapse of 54 months (range, 13-140 months). Five of those 10 patients had a biologic marker and had repeated follow-up material available for MRD monitoring after alloSCT. All 5 patients were negative for MRD in their 2 most recent consecutive follow-up samples. Characteristics of the 20 patients who received allografts are summarized in Table 4. Moreover, there were 4 long-term survivors who lived for >5 years after relapse without undergoing alloSCT. Details of the courses of these 4 patients are summarized in Table 5.

Table 4. Characteristics of Patients Who Underwent Allogeneic Stem Cell Transplantation
SexAge at Relapse, yRFS After AutoSCT, moStatus at AlloSCTAlloSCT RegimenDonorSurvival After Relapse, moFollow-Up
  1. RFS indicates recurrence-free survival; AlloSCT, allogeneic stem cell transplantation; SD, stable disease; MUD, matched unrelated donor; CR, complete remission; TRM, treatment-related mortality; RD, related donor; PR, partial remission; MMUD, mismatched unrelated donor; DLI, donor lymphocyte infusion; b/o, because of; NE, not evaluable.

Man5690SDFludarabine/busulfan/ cyclophosphamideMUD≥52CR
Woman5317CRFludarabine/busulfan/ cyclophosphamideMUD39TRM alloSCT
Man6055PRFludarabine/busulfanMUD15TRM alloSCT
Man4653PRFludarabine/cyclophosphamideMUD≥64CR
Man5242PRFludarabine/cyclophosphamideMUD9TRM alloSCT
Man4316SDMelphalanRD≥140CR
Man5739PRFludarabine/busulfan/ cyclophosphamideMMUD≥95CR
Man3639PRMelphalanMUD33TRM alloSCT
Man594PRMelphalanRD4TRM alloSCT
Man453PRFludarabine/cyclophosphamideRD≥19CR
Man6022PRFludarabine/cyclophosphamideMUD≥53Relapsed, but achieved CR with DLI
Man5922CRFludarabine/cyclophosphamideRD≥13CR
Man5921CRFludarabine/cyclophosphamideMUD≥38CR
Woman374PR2-Gray/fludarabine/ cyclophosphamideMUD19Dead [AQ 15]b/o relapse
Man6315CRFludarabine/busulfan/ cyclophosphamideMMUD≥37CR
Man5632PRFludarabine/cyclophosphamideMUD≥72CR
Man4956PRFludarabine/cyclophosphamideRD≥54CR
Man4627NENENE13TRM alloSCT
Man4919PDFludarabine/cyclophosphamideMUD13TRM alloSCT
Man5212CRFludarabine/cyclophosphamideRD12TRM alloSCT
Table 5. Characteristics of Patients Who Relapsed After Autologous Stem Cell Transplantation and Survived Longer Than 5 Years Even Without Allogeneic Stem Cell Transplantation
Age, ySexTreatment Before AutoSCTRFS After AutoSCT, moSite of Relapse After AutoSCTRelapse TherapyFollow-Up After First Relapse, mo
  1. AutoSCT, indicates autologous stem cell transplantation; RFS, recurrence-free survival; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; Dexa-BEAM, dexamethasone, carmustine, etoposide, cytarabine, and melphalan; Cy-TBI, cyclophosphamide and total body irradiation; R, rituximab; FCM, fludarabine, cyclophosphamide, and mitoxantrone; CR, complete remission; HAM, high-dose cytarabine and mitoxantrone; BEAM, carmustine, etoposide, high-dose cytarabine, and melphalan; DHAP, dexamethasone, high-dose cytarabine, and cisplatin; GemOx, gemcitabine and oxaliplatin; FC, fludarabine and cyclophosphamide; Benda, bendamustine.

62Man4×CHOP; 1×Dexa-BEAM; Cy-TBI+upfront autoSCT36Bone marrow, colon4×R-FCM≥68: Alive in CR with pleural mesothelioma
57Man3×R-CHOP; 1×R-HAM; BEAM+upfront autoSCT39Cervical lymph nodes3×DHAP; 8×R every 3 mo≥76: Alive in CR
58Man4×CHOP; 1×Dexa-BEAM; Cy-TBI+upfront autoSCT42Bone marrow4×CHOP; 1×Dexa-BEAM; R-BEAM+second autoSCT; R-GemOx≥83: Alive in CR
59Woman6×R-CHOP; first relapse, 2×R-HAM; BEAM+salvage autoSCT33Colon4×R every 3 mo; 6×FC; 6× Benda+prednisolone≥85: Alive in CR

Risk Factors for Survival After Relapse

In a log-rank comparison, patients who were free of relapse for at least 1 year after autoSCT had a significantly better OS (median, 41 months) than patients who relapsed within 12 months after autoSCT (median OS, 6 months; P < .0001; HR, 0.01; 95% CI, 0.002-0.04) (Fig. 4B). There was no impact on survival from relapse for the pretransplantation variables upfront versus salvage autoSCT (HR, 1.00; 95% CI, 0.44-2.73) and rituximab versus no rituximab before autoSCT (HR, 0.88; 95% CI, 0.41-1.83). Patients who underwent alloSCT after relapse tended to have better survival than patients who received salvage treatment without alloSCT (P = .06; HR, 0.49; 95% CI, 0.3-1.02) (Fig. 4C). In a multivariate, stepwise, backward Cox model that included the variables alloSCT after relapse, response duration per year after relapse, year of relapse, age at time of relapse, upfront versus salvage autoSCT, and rituximab treatment before autoSCT, the variables response duration after autoSCT (P < .001; HR, 0.45; 95%CI, 0.29-0.68) and alloSCT (P < .01; HR, 0.32; 95%CI, 0.14-0.74) were identified as the only variables that remained in the final models as significant predictors of OS after relapse.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. REFERENCES

The prognosis and survival of patients with MCL have improved considerably during recent years, which may be attributable to high-dose approaches, such as autoSCT, and the availability of rituximab.4, 21 Some authors even have suggested that MCL is curable in a subset of patients by means of rituximab and high-dose ara-C–containing induction regimens followed by autoSCT.12, 22 However, many patients will continue to relapse, but little is known about the patterns and outcome of MCL recurrence after autoSCT. Therefore, we conducted a retrospective analysis of relapse in 118 patients who had undergone autoSCT for MCL, and we analyzed the impact of prognostic factors on the outcome after relapse.

The 5-year incidence of disease recurrence in our cohort was 47%. Relapse risk was significantly lower in patients who underwent first-line rather than salvage transplantation, suggesting that high-dose intensification is much more effective when administered before chemotherapy-resistant clones have evolved. These results are in line with many other reports.5-12

Another important factor that lowered the incidence of relapse after autoSCT in our analysis turned out to be the receipt of rituximab before or during autoSCT. This observation is supported by results from the Nordic Lymphoma Group MCL2 study, which evaluated the impact of a rituximab and high-dose ara-C–containing regimen followed by autoSCT consolidation in 160 untreated patients with MCL,12 and results from other retrospective analyses.14, 22 The 6-year OS and PFS rates in the MCL2 study were 70% and 66%, respectively. Plateaus appeared in both curves, indicating a potential of cure for a subset of patients with this intensive approach. Similarly, we observed a plateau after 5 years for patients who had received rituximab before autoSCT in a previous study.14 The current analysis, which comprises all patients from that study with updated follow-up and some additional patients, confirms and extends the preliminary finding of sustained disease control with first-line autoSCT and rituximab. This is in contrast to the results observed from autoSCT without previous rituximab treatment. The 3 relapses that occurred after >5 years in our cohort were observed exclusively in the group of patients who did not receive rituximab before undergoing autoSCT. However, it has to be taken into account that the follow-up of patients who received rituximab is shorter. A continuous pattern of relapse among patients who underwent autoSCT without previous rituximab treatment also was reported by the Nordic Lymphoma Group for their MCL1 study and in the retrospective analysis by Tam et al.12, 22

Most noteworthy, in our analysis, we were able to demonstrate that the beneficial effect of rituximab treatment was restricted to patients who underwent autoSCT in first remission, indicating that acquired chemoresistance cannot be overcome by rituximab. This is in accordance with a recent update of The University of Texas M. D. Anderson Cancer Center results,24 suggesting that autoSCT remains of limited value for rescuing patients with relapsed MCL also in the rituximab era. These results need to be confirmed in larger studies but may suggest that patients who relapse after conventional first-line therapy should receive an alternative salvage treatment, such as alloSCT, rather than an autoSCT. Other factors, such as high-dose ara-C–containing and TBI-containing conditioning regimens, which reportedly have an impact on patient outcomes after autoSCT for MCL,7, 12, 23, 24 did not produce a reduction in the incidence of disease recurrence in the current analysis.

There are some biologic markers and scoring systems currently under investigation that have demonstrated the ability to predict survival in patients with MCL, such as the MIPI or the proliferation index, as measured by Ki-67 expression in diagnostic samples.25-33 Both parameters were available only for a minority of patients in our retrospective study, which spanned the years from the early 1990s to 2008; therefore, they could not be included in the prognostic factor analysis for the whole population. However, Ki-67 staining in primary lymphoma tissue biopsies was available for 25 of our patients. The median Ki-67 expression was 30% (range, 10%-90%). A univariate Cox regression analysis revealed that the number of K--67-positive MCL cells was correlated with the time to relapse after autoSCT (effect: an increase of 10% in Ki-67-positive cells; P<.01; HR, 1.58; 95% CI, 1.12-2.21). Similarly, MRD monitoring of graft contamination and post-transplantation longitudinal blood and bone marrow samples were available only for a subset of patients from Kiel/Hamburg. The impact of MRD status after autoSCT on the risk of relapse in this series has been published previously.14, 34

With a median survival of 23 months after failure of autoSCT, the outcome of patients with recurrent MCL was poor. The prognosis for patients whose disease recurred within the first year after transplantation was dramatically poor, with a median OS after relapse of only 6 months compared with 41 months for patients who relapsed later. This finding corroborates our findings in patients who relapsed after undergoing autoSCT for follicular lymphoma17 and is in line with observations made in patients with aggressive B-cell lymphoma and chronic lymphocytic leukemia. A short relapse-free interval after autoSCT identifies those patients who have the greatest risk of dying soon after relapse, thereby identifying a population for which aggressive and experimental treatment approaches are justified. However, the outlook for patients who have late relapses also is still dismal and warrants an intensified search for effective salvage strategies.

We were able to demonstrate that alloSCT could induce long-term remission in individual patients with MCL who relapsed after autoSCT. The 2-year OS rate that we observed (59%) is comparable to that reported by the Fred Hutchinson Cancer Center Group for patients with relapsed/refractory MCL, who had a 2-year survival rate after alloSCT of 65%.35 Another retrospective study described an impressively high 3-year OS rate of 85% after alloSCT among patients with relapsed/refractory MCL.36 Although patients in our study who underwent alloSCT had a significantly better OS—;even after adjusting our multivariate analysis for potential confounders—;than those who received treatment without alloSCT, a strong selection bias in favor of alloSCT must be anticipated. Nevertheless, 11 of 20 patients who underwent alloSCT in our study enjoyed long-term survival up to 11 years after relapse, including 5 patients who had MRD markers, all of whom were in molecular remission at the time of this report. Thus, although our data strongly suggest that reduced-intensity conditioning alloSCT can provide long-term disease control in individual patients with recurrent MCL after autoSCT, further studies will be mandatory to confirm conclusions about the overall value of alloSCT in these patients.

It is noteworthy that 4 patients of our patients enjoyed long-term survival even without undergoing alloSCT, and 2 of those patients received only a single salvage immunochemotherapy regimen. All 4 patients belonged to the group that had longer remission duration after autoSCT. This highlights the diversity of different growth patterns of MCL, as also observed in untreated patients,37 and the necessity of valid parameters with which to identify patients who will have an “indolent” disease course after relapse and, thus, may not benefit from alloSCT. However, none of the biologic prognostic markers mentioned above have been validated in the setting of relapsed MCL. Nevertheless, for 1 of our 4 long-term relapse survivors, a lymphoma tissue biopsy was available and revealed only 5% Ki-67 staining, suggesting a low proliferation index of the underlying lymphoma. Thus, the evaluation of prognostic markers in the relapse setting is highly warranted to adapt treatment decisions better to the individual risk profile in MCL.

In conclusion, the outcome of patients who develop recurrent MCL after undergoing autoSCT is poor, especially if their response duration after autoSCT has been short. However, for a subset of patients, alloSCT may offer the possibility of a durable survival, and a few patients may enjoy long-term survival even without undergoing alloSCT. Further studies are needed to provide a scientific rationale for guiding treatment decisions after MCL recurrence after autoSCT.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Conflict of Interest Disclosures
  7. REFERENCES
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