Comparative outcome of initial therapy for younger patients with

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Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: an analysis from the NCCN NHL Database Ann S. LaCasce, MD1, Jonathan L. Vandergrift, MS2, Maria A. Rodriguez, MD3, Gregory A. Abel, MD, MPH1, Allison L. Crosby, MS1, Myron S. Czuczman, MD4, Auayporn P. Nademanee, MD5, Douglas W. Blayney, MD6, Leo I. Gordon, MD7, Michael Millenson, MD8, Ann Vanderplas, MS5, Eva M. Lepisto MSc2, Andrew D. Zelenetz, MD, PhD9, Joyce Niland, PhD5, and Jonathan W. Friedberg, MD10

1Medical Oncology, Dana-Farber Cancer Institute, Boston, MA USA, 2National Comprehensive Cancer Network, Fort Washington, PA, USA 3Lymphoma and Myeloma, M.D. Anderson Cancer Center, Houston, TX, USA 4Medical Oncology and Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA 5City of Hope National Medical Center, Duarte, CA, USA 6Stanford Cancer Center, Stanford, CA USA 7Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 8Fox Chase Cancer Center, Philadelphia, PA, USA, 9Memorial Sloan-Kettering Cancer Center, New York, NY, USA 10James P. Wilmot Cancer Center, University of Rochester, Rochester NY, USA

Corresponding Author: Name: Ann S. LaCasce MD Address: 44 Binney Street, Boston, MA 02115-6084 Email: [email protected] Telephone: 617-632-5959 Fax: 617-632-5890

Running Head: Outcomes of First Line Therapies in MCL

These data were previously presented in abstract form at the 2009 American Society of

Hematology Annual Meeting

Blood First Edition Paper, prepublished online January 10, 2012; DOI 10.1182/blood-2011-07-369629

Copyright © 2012 American Society of Hematology

For personal use only.on January 13, 2019. by guest www.bloodjournal.orgFrom

http://www.bloodjournal.org/

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Abstract

Few randomized trials have compared therapies in mantle cell lymphoma (MCL), and the role

of aggressive induction has not been clearly defined. The NCCN Non-Hodgkin’s Lymphoma

Outcomes Database, a prospective cohort study collecting clinical, treatment, and outcome

data at 7 NCCN centers, provides a unique opportunity to compare the effectiveness of initial

therapies in MCL. Patients younger than 65 with MCL diagnosed between August 2000 and

December 2008 were included if they received RHCVAD, RCHOP+HDT/ASCR,

RHCVAD+HDT/ASCR, or "standard" RCHOP. Clinical parameters were similar for patients

treated with R-HCVAD (n=83, 50%), RCHOP+HDT/ASCR (n=34, 20%), RCHOP (n=29, 17%),

or RHCVAD+HDT/ASCR (n=21, 13%). Overall, 70 (42%) of the 167 patients progressed and

25 (15%) expired with a median follow-up of 33 months. There was no difference in PFS

between aggressive regimens (p>0.57), and all three groups demonstrated superior PFS

compared with RCHOP (p<0.004). There was no difference in OS between the RHCVAD and

RCHOP+HDT/ASCR (p=0.98). RCHOP was inferior to RHCVAD and RCHOP+HDT/ASCR,

which had similar PFS and OS in our patients with MCL. Despite aggressive regimens, the

median PFS was 3 to 4 years. Future trials should focus on novel agents rather than

comparing efficacy of current approaches.




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Introduction

Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin’s lymphoma (NHL),

comprising approximately 5% of all cases. Although recent data demonstrate that the median

survival of MCL has improved over the past decade to approximately five years1, the disease

is not curable with standard therapy and the prognosis remains unfavorable. Few randomized

clinical trials have been conducted in MCL, and the optimal initial therapy has not been

identified.

Although chemotherapy regimens, such as RCHOP, have high response rates in previously

untreated patients with MCL, the durability of remissions is poor2,3. More aggressive initial

therapy is typically favored in younger patients4. R-HyperCVAD5 and standard or dose

intensified chemotherapy followed by high dose therapy and autologous stem cell rescue

(HDT/ASCR) result in improved progression free-survival (PFS) 6-8. These approaches,

however, have not been compared directly in randomized trials.

The National Comprehensive Cancer Network (NCCN) Non-Hodgkin’s Lymphoma (NHL)

Database prospectively collects demographic, treatment and outcome data on patients with

NHL treated at seven NCI-designated cancer centers. The database provides a unique

opportunity to compare the effectiveness of initial treatment approaches in MCL.




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Methods

Patient Cohort

Patients with previously untreated MCL diagnosed between August 2000 and December 2008

were included in the analysis. The NHL component of the NCCN Oncology Outcomes

Database served as the primary source of data. All data utilized in this analysis, including

patient, disease, and treatment characteristics were manually abstracted from medical records

by trained data managers at each participating site.9 Eligibility for the NCCN NHL database are

restricted to newly diagnosed patients >18 years old that are cancer-free for 5 years prior to

diagnosis and have an NHL diagnosis and histology that are confirmed by a

hematopathologist at the treating NCCN center. Participating institutions include; (1) City of

Hope Comprehensive Cancer Center; (2) Dana-Farber/Brigham and Women’s Cancer Center;

(3) Fox Chase Cancer Center; (4) The University of Texas MD Anderson Cancer Center; (5)

Roswell Park Cancer Institute; (6) University of Michigan Comprehensive Cancer Center; and

(7) Robert H. Lurie Comprehensive Cancer Center of Northwestern. Data collection and

storage policies have undergone IRB review and approval at each participating institution. Two

participating centers required individual patient informed consent for participation in

accordance with the Declaration of Helsinki. The remaining participating institutions have

deemed this project to be minimal risk research and have granted waivers for informed

consent due to demonstration of adequate privacy safeguards.

A total of 362 patients with MCL were identified, 242 (67%) of whom were <65 years old.

Patients were further excluded if they: (1) participated in a clinical trial during first-line therapy

(n= 33, 14%); (2) did not receive rituximab as part of first-line therapy (n=32, 13%); (3) did not




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receive CHOP or HyperCVAD as initial induction therapy (n=7, 3%); or (4) received sequential

CHOP and HyperCVAD where the switch in therapy was due to physician preference or

transfer in care (n=3, 1%). After exclusions, 167 patients were included in the final sample

population.

First-line Induction and Consolidation Definitions

The induction component of first-line therapy was defined as the initial chemoimmunotherapy

regimen received within 180 days of diagnosis. Consolidation was defined as HDT/ASCR

initiated within 180 days of induction therapy.

Identification of Survival Events

A PFS event was defined as a (1) patient death, (2) relapse of disease, or (3) an indicator of

disease progression. An indicator of disease progression was defined as a progression

therapy response or discontinuation of therapy noted in the medical record, or the initiation of

second line therapy. PFS event dates were set to either the date of death, documented date

of disease relapse or progression response, or the date of second line therapy initiation.

Overall survival (OS) was determined as a patient death from any cause. Patients without a

PFS event or death were censored at their last follow-up visit to the cancer center. Patient

deaths were identified from the medical record and institutional tumor registry and validated

against the Social Security Death Index and National Death Index databases.




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Definition of Data Elements

Patients were staged using the Ann Arbor staging system. International Prognostic Index (IPI)

scores were computed as outlined by the International Non-Hodgkin's Lymphoma Prognostic

Factors Project10. Comorbidity was assessed using the Charlson Comorbidity Index11.

Cycles of therapy were abstracted from the patient medical record. For the HCVAD regimen,

parts A (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and B (high dose

methotrexate and cytarabine) were considered separate cycles of therapy. Receipt of complete

induction was defined as having received ≥6 cycles of induction therapy. Patients that

progressed while on therapy (n=6) were excluded from all analyses involving cycles of therapy.

A complication of therapy was defined as having at least one associated hospital admission.

Complications treated in the outpatient setting, or that arose while admitted for therapy, were

excluded. Hospital bed days include inpatient days associated with admissions for both

therapy and complications of therapy.

Statistical Analysis

Fisher’s exact test was used to assess the difference between proportions. Significant

differences for interval data were assessed using the Mann-Whitney U-test or Kruskal-Wallis

test. Log-rank tests were used to evaluate differences in survival. Time-to-event analyses were

measured from diagnosis date. All log-rank statistics are reported as two-group tests between

the individual therapy groupings. Multivariable Cox proportional hazard models were used to




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compare outcomes between therapy groups in models adjusted for potential confounding

factors. All statistical tests were two-sided with alpha set at 0.05. All statistical analyses were

conducted using SAS v9.1 (SAS Institute Inc., Cary NC).

Results

Cohort Characteristics

A total of 167 patients were included in the analysis. Demographics are provided in Table 1.

The median age was 56 years (range 29 to 64) with 79% male. Almost all patients were

Caucasian (90%). No statistically significant differences in comorbidity, stage at diagnosis, B

symptoms, or IPI risk group were observed between the four therapy groups, or between the

RHCVAD and RCHOP+HDT/ASCR therapy groups (Table 1). IPI risk group was significantly

associated with overall survival (log-rank p=0.01). Differences in PFS by IPI risk group did not

reach statistical significance (log-rank p=0.07).

First-line Therapy Characterization

Patients received RHCVAD (n=83, 50%), RCHOP+HDT/ASCR (n=34, 20%), RCHOP (n=29,

17%), or RHCVAD+HDT/ASCR (n=21, 13%) as first-line therapy. Therapy selection varied

considerably between institutions (Figure 1). Of the 63 patients receiving RCHOP induction,

three patients (5%) progressed while on therapy, compared with three patients (3%) among

104 who received RHCVAD induction (p=0.67). Some patients received rituximab maintenance

(n=30, 18%) including 2 (7%) in the RCHOP, 11 (13%) in the RHCVAD, 9 (26%) in the

RCHOP+HDT/ASCR, and 8 (38%) in the RHCVAD+HDT/ASCR group (p=0.01). The

difference in R maintenance between RHCVAD and RCHOP+HDT/ASCR was not significantly




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different (p=0.11). Median time to HDT/ASCR following RCHOP (10 weeks,) and RHCVAD (8

weeks) induction were not significantly different (p=0.61). The most common conditioning

regimens used for patients treated with RCHOP+HDT/ASCR were CBV (n=20, 58%),

BEAM/R-BEAM/Z-BEAM (n=6, 18%), Bu/Cy (n=3, 9%), or FTBI/VP/Cy (n=3, 9%). The most

common conditioning regimens used for patients treated with RHCVAD+HDT/ASCR were CBV

(n=9, 43%), BEAM/R-BEAM/Z-BEAM (n=6, 29%), or FTBI/VP/Cy (n=2, 9%). Some patients

received additional drug therapy following initial induction therapy in the RCHOP (n=3, 10%),

RCHOP+HDT/ASCR (n=8, 23%), RHCVAD (n=4, 5%), or RHCVAD+HDT/ASCR (n=1, 5%)

groups without evidence of progression. In most cases patients received one or two cycles of

either RICE, RDHAP, RHCVAD, or RCHOP.

In the RHCVAD group, 79% of patients that did not progress during induction received ≥6

cycles of therapy with 10% having received ≥8cycles (one patient received 10 cycles, Table 2).

In the RCHOP+HDT/ASCR group, 94% of patients received ≥6 cycles of induction compared

with 84% in the RCHOP group (p=0.39). Fewer patients in the RHCVAD+HDT/ASCR therapy

group received ≥6 cycles of induction (n=7, 33%) then in either of the other three therapy

groups (p<0.001 for all pair-wise comparisons).

Overall, 147 (89%) patients had reliable admissions data. Patients receiving RHCVAD required

a more inpatient bed days (median=29) compared to patients who received

RCHOP+HDT/ASCR (median=23, p=0.05, Table 2). Patients receiving RHCVAD+HDT/ASCR

had a median of 53 inpatient bed days which was significantly greater than either the RHCVAD

(p<0.001) or RCHOP+HDT/ASCR (p<0.001) therapy groups.




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Therapy Tolerability

Therapy tolerability was indirectly assessed using two indicators: (1) having received

incomplete induction therapy; or (2) having at least one complication of therapy resulting in

hospitalization (Table 3). The most common complications included febrile neutropenia (n=42,

29%) and infection (n=12, 8%). Rates of febrile neutropenia were highest in the

RHCVAD+HDT/ASCR therapy group (n=7, 44%), followed by the RHCVAD (n=27, 38%),

RCHOP (n=4, 14%), and RCHOP+HDT/ASCR (n=4, 13%) therapy groups

More patients in the RHCVAD (53%, p<0.001) or RHCVAD+HDT/ASCR (75%, p<0.001)

therapy groups had at least one therapy complication requiring hospital admission than

patients receiving RCHOP+HDT/ASCR (16%). The difference in complications requiring

admission between the RHCVAD and RHCVAD+HDT/ASCR therapy groups did not reach

statistical significance (p=0.16), nor did the complication rates between the RCHOP (21%) and

RCHOP+HDT/ASCR therapy groups (p=0.74).

Survival Analysis

Patients alive at the time of censoring were followed for a median of 33 months. Overall, 70

(42%) of the 167 patients had a progression event during the study period including 31 (37%)

in the RHCVAD, 7 (33%) in the RHCVAD+HDT/ASCR, 11 (32%) in the RCHOP+HDT/ASCR,

and 21 (72%) in the RCHOP therapy group. There were no statistically significant differences

in PFS between the RHCVAD, RHCVAD+HDT/ASCR, or RCHOP+HDT/ASCR (> 0.50 for all

pairwise comparisons, Figure 2). Compared with the RCHOP therapy group, the other three

therapy groups demonstrated superior PFS [RHCVAD (p<0.001), RHCVAD+HDT/ASCR




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(p=0.004), and RCHOP+HDT/ASCR (p<0.001)]. Salvage therapy was received by 87% of

patients who progressed or relapsed (n=61). Of those treated, 13 patients were enrolled on

clinical trials, 24 received rituximab plus cytotoxic therapy, 16 received bortezomib (single

agent or combination therapy), and 13 received HDT/ASCR (11 allogeneic and 2 autologous).

Overall, 25 patients (15%) died within the study period including 11 (13%) in the RHCVAD, 5

(15%) in the RCHOP+HDT/ASCR, and 9 (31%) in the RCHOP group (Figure 3). No patients

died within the RHCVAD+HDT/ASCR therapy group. There was no significant difference in OS

between the RHCVAD and RCHOP+HDT/ASCR therapy groups (0.98, Figure 3). The

observed differences in OS between the RCHOP and the RHCVAD (p=0.07) or

RCHOP+HDT/ASCR (p=0.20) therapy groups did not reach statistical significance. Data were

not yet mature enough to include patients treated with RHCVAD+HDT/ASCR in analyses of

OS. The most common cause of death was progressive disease (n=15, 60%), followed by

infection (n=3, 12%), and graft versus host disease (n=2, 25%). One patient receiving

RHCVAD therapy died of renal and liver failure due to excessive toxicity.

PFS and OS were also evaluated using multivariable Cox proportional hazard models to adjust

for potential confounding in patient prognosis between therapy groups. All models were

adjusted for use of rituximab maintenance, IPI, and co-morbidity. No significant difference in

PFS (Hazard Ratio (HR): 0.8, 95% Confidence Interval (CI) [0.4, 1.6], p=0.48) or OS (HR: 1.3,

95% CI [0.5, 4.0], p=0.58) was observed between the RHCVAD (reference) and

RCHOP+HDT/ASCR therapy groups. In addition, no significant difference in PFS was

observed between the RHCVAD+HDT/ASCR therapy group and the RHCVAD (HR: 1.0, 95%




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CI [0.4, 2.4], p=0.92) or RCHOP+HDT/ASCR (HR: 0.8, 95% CI [0.3, 2.1], p=0.67) therapy

groups. RCHOP demonstrated poorer PFS survival compare with RHCVAD (HR: 2.7, 95% CI

[1.6, 4.8], p<0.001), RCHOP+HDT/ASCR (HR: 3.5 95%CI [1.7, 7.4], p<0.001), and

RHCVAD+HDT/ASCR (HR: 2.8, 95%CI [1.2, 6.8], p=0.02). In addition, patients receiving

RCHOP had poorer OS compared with the RHVCAD (HR: 2.5 95% CI [1.0, 6.2], p=0.04). The

difference between RCHOP and RCHOP+HDT/ASCR was not statistically significant (HR: 1.9,

95% CI [0.6, 5.7], p=0.27). Pooling patients in the three intensive therapy groups, both OS

(HR: 0.4, 95% CI [0.2, 0.8], p=0.02) and PFS (HR: 0.3, 95% CI [0.2, 0.6], p<0.001) were

significantly improved versus patients receiving RCHOP alone. Rituximab maintenance was

associated with a statistically significant improvement in PFS (HR: 0.3, 95% CI [0.1, 0.9,

p=0.02]). The association between rituximab maintenance and OS did not reach statistical

significance (HR: 0.6, 95% CI [0.1, 2.6, p=0.50]).

A PFS-sensitivity analysis was performed comparing patients who completed RCHOP without

progression (n=26) and patients who received RCHOP+HDT/ASCR. In this analysis,

RCHOP+HDT/ASCR demonstrated significantly superior PFS to RCHOP (p=0.001).

Discussion

In our study from the NCCN NHL outcomes database, RHyperCVAD, RHyperCVAD followed

by HDT/ASCR, and RCHOP followed by HDT/ASCR had similar disease-specific outcomes.

Patients treated with RCHOP alone had inferior progression-free and overall survival. The

toxicity of the RHyperCVAD arms was greater in terms unplanned hospital admissions, in

particular febrile neutropenia. Although this is not a randomized-controlled trial, patients




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enrolled in the database have similar characteristics to patients reported in clinical trials and

other studies in MCL. The majority of patients in all treatment arms had low or low-intermediate

risk IPI scores. The Mantle Cell Lymphoma International Prognostic Index (MIPI) may be more

relevant than the IPI for patients with MCL12. Recent data validate its predictive value in

patients receiving RHyperCVAD13, as well as those undergoing HDT/ACSR consolidation in

first remission14. We were unable calculate MIPI scores given that not all elements were

included in the database. In addition, the Ki-67 fraction has emerged as a strong predictor of

outcome in MCL but was not examined in all of our NCCN cases15,16.

Recent data from Cornell demonstrated no adverse impact on survival for select patients

undergoing initial observation in MCL17. Our data do not contradict this finding, as all patients

in the current analysis received therapy within 180 days of presentation to the NCCN center.

Outcome for patients receiving RCHOP alone was poor, and median PFS was comparable to

previously published reports2,3. A previously reported retrospective series suggests that

intensive treatment regimens do not yield superior overall survival compared to sequential,

standard therapies18. However our data show a survival disadvantage for younger patients

receiving RCHOP alone, compared to more aggressive regimens.

In terms of patients receiving RHyperCVAD, this study demonstrated inferior PFS (58% at 3

years) and OS (85% at 3 years) compared with published data from the MD Anderson Cancer

Center, where the 3-year failure free survival in patients under 65 was 73%5. When the

regimen was studied by SWOG in the multi-center setting, however, the 2-year failure free

survival was 64% and a significant proportion of patients were unable to receive all the




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planned therapy predominantly due to hematologic toxicity19. These differences are likely due

to patient selection.

The outcome of patients undergoing RCHOP followed by HDT/ASCR in our study was similar

to that reported in the study from Germany by Dreyling, et al7. In this trial, patients were

randomized following standard chemotherapy to high dose chemotherapy with cytoxan/TBI

conditioning versus interferon with a 3 year Event-Free Survival (EFS) of 54% in the transplant

arm. Improved results have been reported by the Nordic group using dose-intensified RCHOP

followed by high dose cytarabine plus rituximab, with 3-year EFS of 70%, although some

patients in this series received pre-emptive therapy at the time of molecular relapse8. It is

unclear whether the more intensive induction therapy in this regimen resulted in prolonged

EFS compared to the German study, where most patients received CHOP or CHOP-like

regimens. In our study, the use of RHyperCVAD prior to transplant did not yield improved PFS

compared with RCHOP followed by transplant or RHyperCVAD, though the number of patients

in each of the transplant arms was small. Our findings are in keeping with a recent analysis of

MCL patients treated at a single institution comparing the impact of a standard versus

intensive induction regimens followed by as the ASCT. The MIPI score was an independent

predictor of survival, and there was not a benefit for intensive regimens after adjusting for

MIPI20. Preliminary results from a large European study, however, comparing RCHOP versus

RCHOP alternating with RDHAP followed by ASCT were recently presented and suggest a

benefit in the RDHAP containing arm. Interestingly, patients who achieved a complete

response after RCHOP had equivalent outcomes to the RDHAP containing arm21. In terms of

maintenance rituximab, we found a significant improvement in progression free survival.




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Preliminary results from a recent study from the MCL Network in patients > 60 who were not

eligible for transplant also demonstrated that maintenance rituximab was associated with

significant prolongation in remission duration compared to interferon or observation22.

The comparison of RHyperCVAD with or without HDT/ASCR, and RCHOP followed by

HDT/ASCR in our study is limited by the fact that this is not a randomized controlled study.

Patients in both transplant arms received a variety of mobilization and conditioning regimens.

There is a possible selection bias in favor of patients receiving RCHOP followed by

HDT/ASCR, as it is difficult to ascertain the treating physician’s plan for each patient at

diagnosis. It is conceivable that for patients starting on RCHOP with the initial intention of

consolidation with high dose therapy, a decision was later made to stop with RCHOP alone,

either due to an inadequate response to therapy, patient comorbidities, or poor chemotherapy

tolerance. However, given the very high response rates observed with RCHOP in MCL this is

unlikely a significant bias in the current study.

This study is also limited by power due to smaller sample sizes among the therapy groups. As

such, differences between the intensive therapy groups may be observed that are not

statistically significant. However, the KM PFS estimates between the three intensive strategies

and the KM OS estimate between the RHCVAD and RCHOP+HDT/ASCR therapy strategies

are very similar and appear clinically insignificant. Therefore, we infer that these strategies

likely have similar disease specific outcomes based on these data.




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When we evaluated the Charlson comorbidity index, as well as median age, there was no

significant difference between the RCHOP alone and the other three arms. Maintenance

rituximab was received by a minority of patients with a greater use in the patients receiving

HDT/ASCR. However, a similar pattern of results were observed in multivariable Cox

proportional hazard models (adjusted for rituximab maintenance, IPI, and comorbidity) as in

the unadjusted KM curves. In addition, the choice of therapy appeared to be more closely

associated with institutional practice, rather than based on patient related or prognostic factors.

The institutions included in the study are all large NCI-designated cancer centers with

experience in delivering high-dose chemotherapy and stem cell transplants. Therefore, while

institutional practice appears to drive therapy selection, it is unlikely that the relationship

between therapy selection and patient outcomes is confounded by the treating institution.

MCL is not a curable disease in most cases, and therefore comparative effectiveness analyses

need to consider therapy-related morbidities and quality of life. Though PFS is a robust

endpoint for clinical benefit23, the toxicity of these regimens was also evaluated. Formal quality

of life assessments are outside the scope of the NCCN NHL database and were not

conducted. Therapy tolerability was indirectly assessed from the number of cycles of treatment

administered and treatment-related toxicities resulting in unplanned hospitalizations.

Tolerability of therapy appeared to be superior in the RCHOP arms. Moreover, although we did

not compare the cost effectiveness of the treatment strategies, aggregate hospital bed days

were analyzed and were greater in both RHyperCVAD arms compared to RCHOP followed by

HDT/ASCR. The overall cost of HDT/ASCR, however, including mobilization of stem cells and

transplantation, may offset the shorter hospital stay in the RCHOP followed by HDT/ASCR




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arm. Future prospective trials including aggressive approaches in mantle cell lymphoma

should include these important secondary endpoints of morbidity and cost.

While these results demonstrate comparable outcomes for patients treated with RHyperCVAD,

with or without HDT/ASCT, and RCHOP followed by HDT/ASCT, neither intensive therapy

strategy seems to result in durable remission of disease. The current randomized study of

RHyperCVAD versus Rituximab plus bendamustine followed by ASCT by the US cooperative

groups will provide definitive evidence regarding the role of intensive induction in younger

patients with MCL. Subsequent future clinical trials should focus on the incorporation of novel

agents, such as bortezomib and lenalidomide, into initial therapeutic regimens, and examine

the role of maintenance strategies. In our cohort, only 14% and 25% of all MCL patients in the

database, all of whom were treated at major cancer centers, participated in clinical trials in the

upfront and relapsed settings respectively. Patient participation in prospective clinical trials is

critical to improve outcomes in MCL.




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Authorship Contributions

Ann S. LaCasce contributed to conception and design, data analysis and interpretation, manuscript writing and final approval of manuscript Jonathan Vandergrift contributed to conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing and final approval of manuscript Maria A. Rodriguez contributed to conception and design, data analysis and interpretation, manuscript writing and final approval of manuscript Gregory A. Abel contributed to conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing and final approval of manuscript Allison L. Crosby contributed to conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing and final approval of manuscript Myron S. Czuczman contributed to conception and design, data analysis and interpretation, manuscript writing and final approval of manuscript Auayporn Nademanee contributed to conception and design, data analysis and interpretation, manuscript writing and final approval of manuscript Douglas W. Blayney contributed to conception and design, data analysis and interpretation, manuscript writing and final approval of manuscript Leo I. Gordon contributed to conception and design, data analysis and interpretation, manuscript writing and final approval of manuscript Michael Millenson contributed to conception and design, data analysis and interpretation, manuscript writing and final approval of manuscript Ann Vanderplas contributed to conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing and final approval of manuscript Eva Lepisto contributed to conception and design, data analysis and interpretation, manuscript writing and final approval of manuscript Andrew D. Zelenetz contributed to conception and design, data analysis and interpretation, manuscript writing and final approval of manuscript Joyce Niland contributed to conception and design, data analysis and interpretation, manuscript writing and final approval of manuscript Jonathan W. Friedberg contributed to conception and design, data analysis and interpretation, manuscript writing and final approval of manuscript




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




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1. Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage Mantle Cell Lymphoma. J Clin Oncol. 2009;27(4):511. 2. Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005;23 (9):1984-1992. 3. Howard OM, Gribben JG, Neuberg DS, et al. Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol. 2002;20(5):1288-1294. 4. NCCN Non Hodgkin’s Lymphoma Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network, Inc, 2010. http://www.nccn.org. Accessed: May 18, 2010. 5. Romaguera JE, Fayad L, Rodriguez MA, et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005;23(28):7013-7023. 6. Damon LE, Johnson JL, Niedzwiecki D, et al. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009;27(36):6101-8. 7. Dreyling M, Lenz G, Hoster E, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005;105(7):2677-2684. 8. Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008;112(7):2687-93. 9. Kho ME, Lepisto EM, Niland JC, et al. Reliability of staging, prognosis, and comorbidity data collection in the National Comprehensive Cancer Network (NCCN) non-Hodgkin lymphoma (NHL) multicenter outcomes database. Cancer. 2008;113 (11):3209-12. 10. A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329(14):987-94. 11. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40(5):373-83. 12. Hoster E, Dreyling M, Klapper W, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111(2):558-65.




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13. Romaguera JE, Fayad LE, Feng L, et al. Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol. 2010;150(2):200-8. 14. Geisler CH, Kolstad A, Laurell A, et al. The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT). Blood. 2010;115(8):1530-3. 15. Determann O, Hoster E, Ott G, et al. Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients treated with anti-CD20 immunochemotherapy: results from randomized trials of the European MCL Network and the German Low Grade Lymphoma Study Group. Blood. 2008;111(4):2385-7. 16. Katzenberger T, Petzoldt C, Holler S, et al. The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma. Blood. 2006;107(8):3407. 17. Martin P, Chadburn A, Christos P, et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009;27(8):1209-13. 18. Martin P, Chadburn A, Christos P, et al. Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard therapies. Ann Oncol. 2008;19(7):1327-1330. 19. Epner EM, Unger J, Miller T, et al. A multi center trial of hyperCVAD+Rituxan in patients with newly diagnosed mantle cell lymphoma. Blood. 2007;110(11):387. 20. Budde, LE, Guthrie, KA, Till, BG, et al. Mantle Cell Lymphoma International Prognostic Index but Not Pretransplantation Induction Regimen Predicts Survival for Patients With Mantle-Cell Lymphoma Receiving High-Dose Therapy and Autologous Stem-Cell Transplantation. J Clin Oncol. 2011;29(22):3023-29. 21. Hermine O, Hoster E, Walewski J, et al. Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Is Superior to 6 Courses CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT In Mantle Cell Lymphoma: Results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net). Blood. 2010;116(21):110. 22. Kluin-Nelemans, JC, Hoster, E, Walewski J, et al. R-CHOP Versus R-FC Followed by Maintenance with Rituximab Versus Interferon-Alfa: Outcome of the First Randomized Trial for Elderly Patients with Mantle Cell Lymphoma. Blood. 2011;118 (21):439. 23. FDA: Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 2007. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071590.pdf. Accessed May 18, 2010.




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Tables & Figures Table 1. Clinical and demographic characteristics of the patient population include in the analysis (n=167). Group (1) (2) (3) (4)

RHCVAD RHCVAD+ RCHOP RCHOP+ HDT/ASCR HDT/ASCR (n=83) (n=21) (n=29) (n=34) P-value

N (%) N (%) N (%) N (%) Total 4-group Group (1) v (4)2 Age at Diagnosis <45 8 (10) 1 (5) 2 (7) 5 (15) 16 (10) 45-54 28 (34) 10 (48) 12 (41) 8 (23) 58 (35) 55-64 47 (57) 10 (48) 15 (52) 21 (62) 93 (56) Median: 56 yrs. 55 yrs. 55 yrs. 56 yrs. 56 yrs. 0.59B 0.46A Charlson Comorbidity Score 0 67 (81) 18 (86) 22 (76) 26 (76) 133 (80) 1 12 (14) 1 (5) 3 (10) 7 (21) 23 (14) 2+ 4 (5) 2 (9) 4 (14) 1 (3) 11 (7) 0.39C 0.66C Stage I/II 2 (2) 0 (0) 3 (10) 1 (3) 6 (4) III/IV 81 (98) 21 (100) 26 (90) 33 (97) 161 (96) 0.22C 1.00C B symptoms at Presentation No 65 (78) 11 (52) 21 (72) 24 (71) 121 (72) Yes 18 (22) 10 (48) 8 (28) 10 (29) 46 (27) 0.13C 0.47C

IPI risk Group L 15 (18) 8 (38) 6 (21) 11 (32) 40 (24) LI 40 (48) 7 (33) 14 (48) 18 (53) 79 (47) HI 20 (24) 5 (24) 8 (28) 5 (15) 38 (23) H 8 (10) 1 (5) 1 (3) 0 (0) 10 (6) 0.30C 0.08C Median Follow-up (months) 33 24 36 33 33 0.63B 0.95B 1“P-value 4-group” refers to the statistical significance across all four therapy groups. 2“Group (1) v (4)” refers to the p-value of the association between patients in the RHCVAD and RCHOP+HDT/ASCR therapy groups.

AMann-Whitney U-test; BKruskal –Wallis test; CFisher’s Exact Test

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Table 2. Number of cycles of induction chemotherapy received and aggregate hospital bed days associated with first-line therapy. Group (1) (2) (3) (4)


N (%) N (%) N (%) N (%) Total 4-group Group (1) v (4) Cycles of Induction Received 1-3 6 (8) 2 (9) 2 (8) 0 (0) 10 (6) 3-5 10 (13) 12 (57) 2 (8) 2 (6) 26 (17) 6 49 (64) 5 (24) 15 (60) 26 (79) 95 (61) 7 4 (5) 0 (0) 2 (8) 4 (12) 10 (6) 8-10 8 (10) 2 (9) 4 (16) 1 (3) 15 (10) NR NR Unknown 3 0 1 1 5 Hospital Days Associated with First-line Therapy 0 0 0 16 (55) 0 16 (11) 1-15 16 (22) 0 11 (38) 0 27 (18) 15-30 21 (30) 0 1 (3) 27 (87) 49 (33) 30-45 29 (41) 5 (31) 0 3 (10) 37 (25) 45+ 5 (7) 11 (69) 1 (3) 1 (3) 18 (12) NR NR Unknown2 12 5 0 3 20 Median: 29 days 53 days 0 days 23 days <0.001***B 0.05*A NR=not reported; 1For patients receiving RCHOP induction, total cycles of therapy includes cycles of sequential therapy received. Patients progressing while on induction therapy (n=6) were excluded from the analysis involving cycles of therapy. 2Unknown hospital days include patients for whom admission records were inaccessible. P-values reflect the difference in median hospital days between the four groups (4-group) or between the RHCVAD and RCHOP+HDT/ASCR groups (group 1 v 4). AMann-Whitney U-test; BKruskal –Wallis test; *** p<0.001, *p<0.05



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Table 3. Indicators of therapy tolerability Group (1) (2) (3) (4)


N (%) N (%) N (%) N (%) Total 4-group Group (1) v (4)2

<6 cycles of induction therapy received No 61 (79) 7 (33) 21 (84) 31 (94) 120 (77) Yes 16 (21) 14 (67) 4 (16) 2 (6) 36 (23) <0.001***C 0.09C Unknown 3 0 1 1 5 Complication(s) of first-line therapy No 33 (46) 4 (25) 23 (79) 26 (84) 86 (58) Yes 38 (53) 12 (75) 6 (21) 5 (16) 61 (41) <0.001***C <0.001***C Unknown 12 5 0 3 20 Indicators of therapy tolerability were examined including receipt of <6 cycles of induction therapy or that had a complication of therapy that required inpatient care or hospitalization. Patients progressing on therapy (n=6) were excluded from all analyses involving cycles of therapy. 1“P-value 4-group” refers to the statistical significance across all four therapy groups. 2“Group 1 v 4” refers to the p-value of the association between patients in the RHCVAD and RCHOP+HDT/ASCR therapy groups. CFisher’s Exact Test; ***p<0.001, **p<0.01, *p<0.05



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Figure Legends:

Figure 1: Institutional variability in the selection of first-line therapy for MCL patients (n=167).

Two institutions that contributed four patients to the study, two from each institution, are not

included in the plot. All four patients received RHCVAD.

Figure 2: KM estimates of Progression-free Survival (PFS) from diagnosis by therapy group.

Log-rank statistics were used to compare the four therapy groups. No significant difference was

observed between the RHCVAD and RCHOP+HDT/ASCR therapy groups (p=0.50), or between

the RHCVAD (p=0.57), RCHOP+HDT/ASCR (p=0.96), and RHCVAD+HDT/ASCR therapy

groups. Patients in the RHCVAD (p<0.001), RHCVAD+HDT/ASCR (P=0.004), and

RCHOP+HDT/ASCR (p<0.001) therapy groups had significantly superior PFS compared with

patients in the RCHOP therapy group. Median follow-up: 33 months. 3yr-PFS: RHCVAD=58%

(95% Confidence Interval (CI), [44%, 69%]), RCHOP+HDT/ASCR=56% (95% CI, [33%, 74%]),

RHCVAD+HDT/ASCR=55% (95% CI, [22%, 79%]), RCHOP=18% (95% CI, [6%, 36%])

Figure 3: KM estimates of Overall Survival (OS) from diagnosis by therapy group. Log-rank

statistics were used to compare the three therapy groups. No significant difference was

observed between the RHCVAD and RCHOP+HDT/ASCR (p=0.98) or between the

RCHOP+HDT/ASCR and RCHOP (p=0.20) therapy groups. Patients in the RHCVAD therapy

group had marginally greater OS than those in the RCHOP therapy group (p=0.07). Data were

not yet mature enough to examine survival for patients receiving RHCVAD +HDT/ASCR.

Median follow-up: 33 months. 3yr-OS: RCHOP+HDT/ASCR=87% (95% Confidence Interval

(CI), [64%, 95%]), RHCVAD=85% (95% CI, [74%, 92%]), RCHOP=69% (95% CI, [46%, 83%]).




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Figure 1



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FS

Years from Diagnosis

RCHOP+HDT/ASCR (n=34, censored=23)

RHCVAD (n=83, censored=52)

RHCVAD+HDT/ASCR (n=21, censored=14)

RCHOP (n=29, censored=8)

RCHOP 29 17 8 3 3 1 1 1 1

RCHOP+HDT/ASCR 34 28 18 9 3 2 1 0 0

RHCVAD 83 59 40 24 17 5 1 1 1

RHCVAD+HDT/ASCR 21 19 11 5 5 4 3 2 0

Figure 2



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OS

Years from Diagnosis

RCHOP+HDT/ASCR (n=34, censored=29)

RHCVAD (n=83, censored=72)

RCHOP (n=29, censored=20)

RCHOP 29 23 18 11 8 4 4 3 1

RCHOP+HDT/ASCR 34 29 23 15 7 3 1 0 0

RHCVAD 83 63 45 33 22 12 4 1 1

Figure 3



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doi:10.1182/blood-2011-07-369629Prepublished online January 10, 2012;

Vanderplas, Eva M. Lepisto, Andrew D. Zelenetz, Joyce Niland and Jonathan W. FriedbergS. Czuczman, Auayporn P. Nademanee, Douglas W. Blayney, Leo I. Gordon, Michael Millenson, Ann Ann S. LaCasce, Jonathan L. Vandergrift, Maria A. Rodriguez, Gregory A. Abel, Allison L. Crosby, Myron cell lymphoma: an analysis from the NCCN NHL DatabaseComparative outcome of initial therapy for younger patients with mantle

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