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Published in final edited form as: Biol Blood Marrow Transplant. 2015 Sep 5;22(2):380–385. doi: 10.1016/j.bbmt.2015.08.035

Pretransplant minimal residual disease predicts survival in mantle cell lymphoma patients undergoing autologous stem cell transplantation in complete remission

Andrew J Cowan 1, Philip A Stevenson 1, Ryan D Cassaday 1, Solomon A Graf 1, Jonathan R Fromm 2, David Wu 2, Leona A Holmberg 1, Brian G Till 1, Thomas R Chauncey 1,3, Stephen D Smith 1, Mary Philip 1, Johnnie J Orozco 1, Andrei R Shustov 1, Damian Green 1, Edward N Libby III 4, William I Bensinger 1, Mazyar Shadman 1, David G Maloney 5, Oliver W Press 1, Ajay K Gopal 1
PMCID: PMC4716882  NIHMSID: NIHMS721412  PMID: 26348890

Abstract

Autologous stem cell transplantation (ASCT) is standard therapy for mantle cell lymphoma (MCL) in remission following induction chemotherapy with the best results for patients in complete remission (CR). We hypothesized that evaluation of MRD prior to ASCT could further stratify outcomes for these patients. Patients with MCL who underwent ASCT in clinical CR between 1996 and 2011, with pretransplant MRD testing were eligible. Presence of a clonal IgH rearrangement, t(11;14) by PCR, or positive flow cytometry from blood or bone marrow was considered positive. An adjusted proportional hazards model for associations with progression-free (PFS) and overall survival (OS) was performed. Of 75 MCL patients in CR, 8 (11%) were MRD positive. MRD positivity was associated with shorter OS and PFS. The median OS for MRD-negative patients was not reached with 82% survival at 5 years, while for the MRD-positive patients was 3.01 years (hazard ratio [HR] 4.04, p = 0.009), with a median follow-up of 5.1 years. The median PFS for MRD-negative patients was not reached with 75 % PFS at 5 years, while for MRD-positive patients was 2.38 years (HR 3.69, p = 0.002). MRD positivity is independently associated with poor outcome following ASCT for MCL patients in CR.

Keywords: Mantle cell lymphoma, transplant, minimal residual disease, predictors, survival

Introduction

Mantle cell lymphoma (MCL) is an aggressive lymphoma, representing approximately 6% of all lymphomas in the US, with a median survival of greater than 5 years (1, 2). The majority of patients with MCL are male and present at a median age of 68 (2, 3). The t(11;14)(q13;q32) chromosomal translocation is characteristic of MCL and juxtaposes the CCND1 gene in close proximity to the immunoglobulin heavy chain (IGH) gene locus, resulting in overexpression of cyclin D1 (4). While some patients may present with indolent disease, in general, MCL has an aggressive course, and most patients are found to have stage III to IV disease (2). Historically, MCL has been associated with a poorer prognosis than many other lymphomas (2). Over the last decade, there has been dramatic improvement in the management of patients with MCL – with the advent of advances in transplantation, targeted novel therapies, and improved understanding of the molecular biology of MCL.

Typically, front-line management of MCL takes a risk-adapted approach, reserving the most intensive approach with high-dose therapy followed by autologous stem cell transplantation for younger, fitter patients, while treating elderly patients with less toxic regimens (2, 5). Several important clinical trials have established ASCT as a standard of care for mantle cell lymphoma. The first randomized study by Dreyling et al, in 2005, compared induction chemotherapy with CHOP followed by autologous transplantation or interferon alpha (IFN) maintenance, and described a progression free survival of 54% for ASCT vs 25% for IFN at 3 years, a statistically significant difference (6). Subsequent studies performed by the Nordic lymphoma group, the Cancer and Leukemia Group B (CALGB), and the European MCL network have confirmed prolonged disease control with intensive induction and ASCT, although not in the context of a randomized trial (7-9). Accordingly, major societies such as the EBMT and EMCL have concluded that upfront ASCT for patients in remission after induction immunochemotherapy should be the standard of care for younger patients with MCL (10).

Although intensive induction followed by ASCT results in durable remissions for many, a significant proportion have disappointing outcomes. Investigations into predictors for patients with MCL undergoing ASCT have been studied; among those studied have been the Mantle Cell Lymphoma International Prognostic Index (MIPI), positron emission tomography-computed tomography (PET-CT) imaging, and measurement of minimal residual disease (MRD). The MIPI was created using a regression analysis of a clinical trial database, and was shown to be a useful prognostic tool (11, 12). More recent studies have confirmed that the MIPI is also predictive of outcomes after transplant, and when applied to the results of the Nordic MCL2 trial, both the MIPI and the simplified MIPI were demonstrated to be superior to the IPI in predicting survival after ASCT (13-15). In several series, PET-CT assessment prior to transplant has been shown to be a good predictor of outcomes after transplant (16-19). Taken together with other data in non-Hodgkin lymphoma, the recent update of the Lugano Classification included PET-CT with standard staging, emphasizing the importance of this new modality in staging and assessment of disease response (20).

Limited data exist regarding the use of polymerase chain reaction (PCR) amplification of immunoglobulin heavy chain rearrangements or flow-cytometry-based minimal residual disease (MRD) measures and outcome in MCL(21-23). These studies only included patients in prospective clinical trials using patient-specific PCR assays, and few data exist regarding the application of this strategy to an unselected population of MCL patients undergoing ASCT when routine clinical testing is employed. We sought to address the hypothesis that clinical MRD testing would be predictive of outcome by analyzing the association standard MRD assay results with outcomes in an unselected cohort of MCL patients undergoing ASCT in CR at our institution.

Methods

Patients

Sequential patients older than 18 years of age with confirmed diagnosis of MCL, who underwent ASCT between 1996 and 2011 at the Fred Hutchinson Cancer Research Center (FHCRC), University of Washington Medical Center, and Veterans Affairs Puget Sound Healthcare System (Seattle, Washington, USA) were eligible. Patients treated on an investigational study had signed a consent form authorized by the Human Subjects Committee of the University of Washington and/or the Institutional Review Board of the FHCRC in accordance with the Declaration of Helsinki. Separate institutional approval was also obtained to gather retrospective data from patient records and databases.

Study Variables

We collected baseline demographic data and patient characteristics at the time of diagnosis and at the time of ASCT – including age, presence of B symptoms (fever, night sweats, or >10% unintentional weight loss), number and type of treatments received prior to ASCT; and post-transplant – whether or not patients received maintenance rituximab. Simplified MIPI scores were calculated using data available at time of diagnosis (11). Data on type of MRD analysis specimen and type of analysis were collected; presence of a clonal IGH rearrangement or t(11;14) IGH/CCND1 fusion by PCR, or positive flow cytometry from blood, bone marrow, or apheresis products prior to transplant was scored as MRD positive. Complete remission (CR), overall survival (OS) and progression-free survival (PFS) were defined by standard criteria (24).

Treatment

For this retrospective study, patients who received either conventional conditioning regimens or radioimmunotherapy based (RIT) regimens were included. Conventional regimens comprised either carmustine, etoposide, cytarabine, and melphalan (BEAM); busulfan, melphalan, and thiotepa (BuMelT); or cyclophosphamide with or without etoposide in combination with 12 Gray of total body irradiation (TBI), as previously documented (25, 26). RIT was given either alone or with increasing doses of fludarabine or with cyclophosphamide and etoposide (27-29).

Flow cytometry

Multiparameter flow cytometry was used to assess MRD and are described in detail elsewhere (30-32). Specimens were prepared by pre-lysis (with ammonium chloride) or simultaneously lysed and fixed (with ammonium chloride and formaldehyde), stained with antibodies and run on the flow cytometer as described in prior publications from our group (33). Data were analyzed using custom, in house software as described elsewhere (33). The sensitivity to detect minimal residual disease is ∼ 1 in 10,000 cells and dependent on the number of analyzed events by flow cytometry, which typically was greater than 200,000 viable events per sample.

PCR-based MRD assessment

Purification of DNA for PCR used either EZ1 Advanced XL solution (Qiagen, Venlo, Netherlands) or Puregene DNA Isolation kit (Gentra Systems, Minneapolis, MN, USA). Samples were analyzed for B cell clonality by PCR using testing for immunoglobulin heavy chain (IGH) and in some cases kappa light chain gene (IGK) rearrangement employing a method developed by the European BIOMED-2 Concerted Action study group (34). PCR products are subsequently evaluated by capillary electrophoresis. The sensitivity of detecting a clonal IGH or IGK is approximately 2 to 5%, and is dependent on the background number of B or plasma cells in the sample, in addition to the amount and quality of input DNA.

The assay used for detection of t(11;14), (IGH-CCND1), uses a nested PCR with primers directed against the major translocation cluster (MTC) of breakpoints in the CCND1 locus on chromosome 11, coupled with consensus primers directed against the J regions of the IGH gene on chromosome 14. PCR products are evaluated by gel electrophoresis and visualized with ethidium bromide staining. The sensitivity for detection of the t(11;14) fusion by nested-PCR ranges in this clinical assay ranges from 1 in 10,000 to 1:30,000, dependent on the amount and quality of the input DNA.

Statistical considerations

Survival analysis using Kaplan-Meier curves were generated to estimate the OS and PFS from the time of ASCT. Minimal residual disease, along with clinical factors was evaluated in an adjusted Cox proportional hazards regression model for associations with progression-free (PFS) and overall survival (OS).

Results

Patient Characteristics

We identified seventy-five patients with MCL who were in a complete remission at the time of ASCT, and who subsequently underwent ASCT, between the years 1996 and 2011. The baseline demographics and patient characteristics of all patients, as well as those with MRD positive and negative statuses, are depicted in Table 1. The median age at the time of transplant was 58 years (range, 38-71) for all patients, and the majority of the patients were male. The median time from diagnosis to initial induction treatment was 1 month (range, 0 – 12 months), and a minority of patients (n=17) had B symptoms at diagnosis (23%). Of evaluable patients, 26 (41%) had a simplified MIPI between 0 – 2, and 37 (59%) had a simplified MIPI greater than 2 (59%). The majority of patients received rituximab within 3 months of ASCT. Initial induction chemotherapy regimens included HyperCVAD in 37 patients (49%), CHOP in 35 (47%), CVP in 1 (1%), cyclophosphamide in 1(1%), and maxi-CHOP in 1 (1%). Most patients in our cohort were undergoing ASCT in first remission (n=65, 87%), and almost half received post-transplant maintenance rituximab (n=34, 45%). There were 6 patients with blastoid variants of MCL; of these, 5 were in the MRD-negative group, and 1 was in the MRD-positive group. Of all the patients in our cohort, only 40 patients underwent pre-transplant PET-CT studies, and all were negative.

Table 1.

Demographics and patient characteristics for patients in complete remission prior to high-dose therapy and autologous stem cell transplantation.

Characteristic All patients (n=75) MRD neg (n=67) MRD pos (n=8)
Male (%) 59 (79) 53 (79) 6 (75)
Median age at time of transplant (range) 58 (38 - 71) 58 (38 - 71) 62.5 (53 - 70)
Diagnosis to Treatment (mos) 1 (0 - 12) 1 (0 - 12) 1 (0 - 2)
B symptoms at diagnosis (%) 17 (23) 16 (24) 1 (13)
sMIPI at diagnosis (% of evaluable)
 0 - 2 26 (41) 24 (42) 2 (33)
 >= 3 37 (59) 33 (58) 4 (67)
Chemosensitive disease (%) 75 (100) 67 (100) 8 (100)
Rituximab pre-ASCT (%) 73 (97) 65 (97) 8 (100)
Rituximab-chemotherapy within 3 months of ASCT (%) 63 (84) 56 (84) 7 (88)
Initial chemotherapy (%)
 HyperCVAD 37 (49) 34 (51) 3 (38)
 CHOP 35 (47) 30 (45) 5 (63)
 CVP 1 (1) 1 (1) 0 (0)
 Cyclophosphamide 1 (1) 1 (1) 0 (0)
 Maxi-CHOP 1 (1) 1 (1) 0 (0)
MRD Analysis Type (%)
 IGH PCR 40 (53) 40 (60) 0 (0)
 t(11;14) PCR 19 (25) 13 (19) 6 (75)
 Flow cytometry 16 (21) 14 (21) 4 (50)
MRD Analysis Specimen (%)
 Bone marrow aspirate 63 (84) 58 (87) 5 (63)
 Peripheral blood 8 (11) 5 (7) 3 (37)
 Apheresis product 4 (5) 4 (6) 0 (0)
First remission (%) 65 (87) 59 (88) 6 (75)
Post ASCT rituximab maintenance (%) 34 (45) 29 (43) 5 (63)
PET-CT Performed (%) 40 (53) 36 (54) 4 (50)
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MRD-Negative Patients

Of the patients identified, 67 (89%) were found to be MRD-negative prior to ASCT. The majority were male (n=35, 79%), and the median age was 58 years (range, 38-71 years). At diagnosis, 24 patients (41%) had a simplified MIPI of 0-2, and 37 patients (58%) had a simplified MIPI of greater than 2.Fiftysix patients (84%) had received rituximab-chemotherapy within 3 months of undergoing ASCT. The initial chemotherapy was HyperCVAD in 34 patients (51%), and CHOP in 30 patients (45%). The majority of patients, 59 (88%), were in first CR. Thirty-six patients (54%) had PET-CT studies performed, and all were negative.

MRD-Positive Patients

Eight patients (11%) were found to be MRD-positive at the time of ASCT. The majority were male, with a median age of 62.5 years (range, 53 – 70). At diagnosis, 2 patients (33%) had a simplified MIPI of 0 – 2, and 4 patients (67%) had a simplified MIPI of greater than 2. Of the 8 patients, 7 (88%) had received rituximab-chemotherapy within 3 months of ASCT. The initial chemotherapy received was CHOP in 5 (63%), and HyperCVAD in 3 (38%). Six of the 8 MRD positive patients (75%) were transplanted in first remission. Four patients (50%) had PET-CT testing performed; all were negative.

MRD Analysis

Modalities available for assessment of MRD prior to ASCT included PCR for the clonal IGH rearrangement, PCR for the t(11;14) translocation, and flow cytometry. The presence of a clonal IGH rearrangement by PCR, t(11;14) by PCR, or positive flow cytometry from bone marrow aspirate, peripheral blood, or apheresis product were scored as positive for MRD. For all patients, methods used included IGH PCR in 40 (53%), t(11;14) PCR in 19 (25%), and flow cytometry in 16 (21%) (Table 1). Of the 8 patients who were positive for MRD, methods included t(11;14) PCR in 6 patients (75%) and flow cytometry in 4 patients (50%) (2 patients were positive for MRD by both PCR for t(11;14) and flow cytometry; 5 patients had IGH PCR performed and all were negative). Methods used in the MRD-negative patients included IGH PCR in 40 (60%), t(11;14) PCR in 13 (19%) and flow cytometry in 14 (21%).

For all patients, the most frequent specimen on which MRD analysis was performed was bone marrow aspirate in 63 patients (84%), followed peripheral blood in 8 (11%), and apheresis product in 4 (5%). For the MRD-positive patients, positive specimens included bone marrow aspirate in 5 (63%) and peripheral blood in 3 (37%). For the MRD-negative patients, specimens tested included bone marrow aspirate in 58 (87%), peripheral blood in 5 (7%), and apheresis product in 4 (6%).

Survival analysis and Proportional Hazards Model

The presence of MRD in patients with CR was associated with both OS and PFS. The median OS for MRD-negative patients was not reached with 82% survival at 5 years, while for the MRD-positive patients it was 3.01 years (p=0.009, as calculated by log-rank analysis), with a median follow-up of survivors of 5.1 years. The median PFS for MRD-negative patients was not reached with 75% PFS at 5 years, while for the MRD-positive patients it was 2.38 years (p=0.002, as calculated by log-rank analysis). Kaplan-Meier plots were created for both the MRD-negative and MRD-positive patients in CR at the time of ASCT, and are depicted in Figure 1. In order to adjust for the potential impact of rituximab on MRD depletion of the blood and bone marrow, identified as a significant confounder based on univariate analysis, we then performed a Cox-proportional hazards analysis to adjust for the impact of rituximab within 3 months of transplant (Table 2). Our ability to add additional covariates into the multivariate model was limited by the small number of MRD positive patients. Even after adjustment for the receipt of rituximab within 3 months we still found a 4 fold higher risk for death in the MRD-positive patients (Hazard ratio [HR] 4.043, 95% CI, 1.429 to 11.442, p=0.0085), and a 3.5 fold higher risk for relapse or death in the MRD-positive patients (Hazard ratio [HR] 3.686, 95% CI, 1.546 to 8.789, p=0.003).

Figure 1.

Figure 1

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Kaplan-Meier plots for (a) progression-free survival, and (B) overall survival for MRD-negative and MRD-positive patients in CR. Kaplan-Meier plots were calculated from the time of autologous stem cell transplantation.

Table 2. Adjusted Proportional Hazards Model for MRD Positivity pre-ASCT for MCL*.

Cox adjusted proportional hazards model of overall survival and progression-free survival for patients in complete remission with MRD-negative and MRD-positive status prior to high-dose therapy and autologous stem cell transplantation.

PFS
Hazard ratio (CI) p value
MRD+ 4.04 (1.43 - 11.44) 0.0085
OS
Hazard ratio (CI) p value
MRD+ 3.68 (1.55 - 8.79) 0.0033
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*

Adjusted for receipt of rituximab within the past 3 months

Of the MRD positive patients, 5 received post-transplant maintenance rituximab (MR) and 3 did not. The median OS of the MRD positive patients who received MR was 63 months (95% CI, 28 months to NA), and the median OS for the MRD positive patients who did not receive MR was 36 months (95% CI, 30 months to NA). Three patients who were MRD positive received HyperCVAD, and 5 patients received CHOP. The median OS for the 3 patients who received HyperCVAD was 28 months (95% CI, 18 months to NA), and the median OS for the 5 patients who received CHOP was not reached (95% CI, 63 months to NA).

Discussion

In summary, we analyzed retrospective data from a single academic center looking at an unselected cohort of 75 patients with mantle cell lymphoma, who were in complete remission prior to undergoing high-dose therapy and ASCT. The majority of patients in this series were MRD-negative, with only 8 MRD-positive patients. The outcomes for the MRD-positive patients were strikingly different from the MRD-negative patients, with a median overall survival of 3.01 years (p=0.009) compared with the MRD-negative patients who did not reach the median overall survival with 5.1 years of follow-up. In routine clinical care of our patients prior to undergoing high-dose therapy and ASCT, we typically perform both PCR-based assays and flow cytometry; in this current series, of the 8 MRD positive patients, 6 were identified using PCR for t(11;14), and flow cytometry in 2 patients. To attempt to adjust for any confounding covariates, we performed a Cox proportional hazards model, and adjusting for receipt of rituximab within the 3 months prior to evaluation the HR for OS was 4.043 (p=0.009) and the HR for PFS was 3.686 (p=0.003), demonstrating that even with adjustment, MRD-positive patients have a significantly worse outcome. Given that the presence of rituximab at the time of MRD measurement could reduce our ability to detect a B-cell clone, the adjustment for rituximab receipt had some biological plausibility.

Our results are generally in keeping with the published literature to date on the value of MRD assessment in MCL. The European MCL network has published data generated from large clinical trials examining the impact of MRD both after induction chemo-immunotherapy and following ASCT (22, 23). In the first large study, the relationship between MRD status and outcomes was shown to be predictive of poorer outcomes in a multivariable model (23). Further data from the European MCL Younger and Older studies (in which approximately half of the patients underwent high dose therapy and ASCT), showed that presence of a molecular remission identified using allele-specific oligonucleotide (ASO) primers with real-time quantitative (RQ) PCR after induction chemo-immunotherapy was highly predictive of outcome after ASCT for those who received it, and during maintenance therapy for those who did not proceed to ASCT (22). Another analysis of MRD was performed on patients enrolled in the CALGB 59909 study, in which MRD assessments were performed following induction therapy; detection of MRD was associated with worse outcomes after transplant, even in a multivariable model (21). In contrast to the aforementioned studies, which were performed within the context of a clinical trial, our analysis is of an unselected cohort of mantle cell lymphoma patients. Thus, a strength of our study is that we show that MRD assessment is impactful even outside the controlled environment of a clinical trial.

Prior studies that have examined the impact of MRD assessment in MCL have almost exclusively been conducted in the context of clinical trials, using ASO RQ-PCR, which has the advantages of being a highly sensitive, quantitative technique. While these techniques offer high sensitivity for MRD assessment, for the vast majority of hospitals, clinics, and laboratories, these specialized techniques are not available, especially in the United States (US). We did not use an ASO RQ-PCR assay in this study; while acknowledging the drawbacks of consensus PCR, a strength of our study is that we demonstrate the applicability of more general, non-research PCR based methods as well as clinical flow cytometry in the assessment of MRD prior to autologous transplantation, and also confirmed the impact of MRD positivity on survival and outcomes outside the context of a clinical trial. Patients were drawn from both a large, tertiary referral cancer center, and also a Veterans Affairs hospital, increasing the heterogeneity and the potential generalizability of the population examined.

In contrast to the studies by the European MCL network and others, our study identified fewer MRD positive patients (8 of 75, 11%), of these, the majority had a positive test resulting from PCR analysis for t(11;14), while only 2 patients had positive tests confirmed only by flow cytometry – 2 patients had MRD testing confirmed both by t(11;14) PCR and flow cytometry. These finding are likely in part due to the use of clinical assays in our study for determination of residual disease and the lack of allele-specific PCR primers. These results, however, emphasize that potential utility of molecular and flow cytometry assessment as part of routine clinically available assessments based on the observed strong associations with outcome.

In summary, our results further support the value of MRD assessments, in this series of patients with advanced mantle cell lymphoma prior to ASCT, from an unselected cohort of patients seen at a tertiary referral center. Measurement of MRD could be tested in the future as a method for risk stratification and offering patients different treatment algorithms based on results of testing, as has been done with other hematologic malignancies to identify a target population where novel agents such ibrutinib or lenalidomide or strategies such as tandem autologous- followed by non-myeloablative transplants can be first assessed. Conversely, since MRD-negative patients have excellent outcomes in general; it is possible that these patients may benefit less from additional post-transplant therapies. Until prospective studies using MRD measures to test these hypotheses are completed our data would suggest that these measures at a minimum can be used stratify the risk of recurrence for MCL patients undergoing autologous transplantation in complete remission.

  • Autologous stem cell transplantation is standard therapy for mantle cell lymphoma.

  • We hypothesize that minimal residual disease could stratify outcomes for transplant.

  • Minimal residual disease (MRD) positivity was associated with shorter OS and PFS.

  • MRD positivity is independently associated with poor outcome following transplant.

Acknowledgments

A.J.C. is supported by 5T32HL007093. This work was supported by research funding from NIH P01CA044991 and K24CA184039; Lymphoma Research Foundation Mantle Cell Lymphoma Research Initiative Clinical Scholar Award by the Leukemia and Lymphoma Society to A.K.G.; the Mary Aileen Wright Memorial Fund; the David and Patricia Giuliani Family Foundation; and philanthropic gifts from Frank and Betty Vandermeer and Don and Debbie Hunkins.

Footnotes

Conflict of Interest: The authors of this paper have no relevant conflicts of interest to disclose.

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