Phase 2 Trial of Rituximab Plus Hyper-CVADAlternating With Rituximab Plus Methotrexate-Cytarabine for Relapsed or RefractoryAggressive Mantle Cell Lymphoma

Michael Wang, MD1

Luis Fayad, MD1

Fernando Cabanillas, MD2

Fredrick Hagemeister, MD1

Peter McLaughlin, MD1

Maria A Rodriguez, MD1

Larry W. Kwak, MD1

Yuhong Zhou, MD3

Hagop Kantarjian, MD4

Jorge Romaguera, MD1

1 Department of Lymphoma & Myeloma, The Uni-versity of Texas M. D. Anderson Cancer Center,Houston, Texas.

2 Department of Medical Oncology, King JuanCarlos I Cancer Center, Auxilio Mutuo Hospital,San Juan, Puerto Rico.

3 Department of Medical Oncology, ZhongshanHospital, Department of Oncology, ShanghaiMedical College, Fudan University, Shanghai,China.

4 Department of Leukemia, The University ofTexas M. D. Anderson Cancer Center, Houston,Texas.

BACKGROUND. Relapsed or refractory mantle cell lymphoma has a very poor

prognosis. The authors evaluated the response rates and survival times of

patients treated with an intense regimen known to be effective against untreated

aggressive mantle cell lymphoma: rituximab plus hyper-CVAD (cyclophospha-

mide, vincristine, doxorubicin, and dexamethasone) alternating with rituximab

plus methotrexate-cytarabine.

METHODS. In this prospective, open-label, phase 2 study, patients received this

combination for 6 to 8 cycles. Twenty-nine patients were evaluable for response.

RESULTS. The median number of cycles received was 5 (range, 1-7 cycles), and

the overall response rate was 93% (45% complete response [CR] or CR uncon-

firmed [CRu] and 48% partial response [PR]). All 5 patients previously resistant to

treatment had a response (1 CR, 4 PR), and both patients whose disease did not

change in response to prior therapy had PRs. Toxic events occurring in response

to the 104 cycles given included neutropenic fever (11%), grade 3 or 4 neutrope-

nia (74%), and grade 3 or 4 thrombocytopenia (63%). There were no deaths from

toxicity. At a median follow-up of 40 months (range, 5-48 months), the median

failure-free survival time was 11 months with no plateau in the survival curve.

CONCLUSIONS. This combination chemotherapy was effective for refractory/

relapsed mantle cell lymphoma. Cancer 2008;113:2734–41. � 2008 American

Cancer Society.

KEYWORDS: mantle cell lymphoma, hyper-CVAD, rituximab, survival rates,response rates.

M antle cell lymphoma (MCL) currently has the worst prognosis of

all malignant lymphomas. Among patients with newly diagnosed

MCL who receive standard chemotherapy, complete response (CR)

rates range from 21% to 40%, median failure-free survival duration is

10 to 16 months, and median overall survival duration is 3 years1-7

Relapsed or refractory MCL has a poor outcome after autolo-

gous stem-cell transplantation.8 The recent use of nonmyeloablative

allogeneic stem-cell transplantation has demonstrated promising

Luis Fayad is a speaker for and receivesresearch support from Genetech.

Peter McLaughlin receives research support fromBerles, Biogen IDEC, Genentech, Shering-Plough,Integrated Therapeutics, OSI, Millennium, andBayer. In addition, he is a consultant to Millen-nium and Berlex and is on the speakers’ bureausof Co-Med Communications, Physicians Educa-tion Resource, Cogenix, and Health Science Com-munications.

Jorge Romaguera designed and performed theresearch for this article. Michael Wang performedresearch, contributed vital new reagents or ana-lytical tools, analyzed data, and wrote this article.The remainder of the authors performed researchand contributed patients to the clinical trial.

We would like to thank Bonnie Baum for typingthis article.

Address for reprints: Jorge E. Romaguera, MD,Department of Lymphoma and Myeloma, TheUniversity of Texas M. D. Anderson Cancer Center,

1515 Holcombe Boulevard, Unit 429, Houston, TX77030; Fax: 713-794-5656; E-mail: jromague@mdanderson.org

Received April 8, 2008; revision received May23, 2008; accepted June 3, 2008.

ª 2008 American Cancer SocietyDOI 10.1002/cncr.23880Published online 20 October 2008 in Wiley InterScience (www.interscience.wiley.com).

2734

2-year continuous progression-free survival,9 suggest-

ing a graft-versus-lymphoma effect. The best out-

comes are reserved, however, for patients who

achieve a CR after salvage therapy. Thus, the effec-

tiveness of the salvage regimen given before stem-

cell transplantation is crucial to the success of these

transplants and important to improvement of patient

of survival rates.

Intensive therapies that have shown activity in

other MCL settings may be applicable to relapsed or

refractory disease. In particular, rituximab in combi-

nation with hyper-CVAD (cyclophosphamide, vincris-

tine, doxorubicin [Adriamycin], and dexamethasone)

alternating with rituximab plus methotrexate-cytara-

bine has resulted in an 87% CR rate among untreated

patients with aggressive MCL.10 A logical next step is

introduction of this regimen in the management of

relapsed or refractory MCL. We report here the

results of a phase 2, prospective, clinical trial of this

regimen in relapsed or refractory MCL.

MATERIALS AND METHODSPatient EligibilityPatients with relapsed or refractory aggressive MCL

were recruited and then, if eligible and after signing

an informed consent form, were enrolled in this phase

2 prospective clinical trial at the University of Texas

M. D. Anderson Cancer Center. The study design was

approved by the institutional review board.

Patients eligible for inclusion in the study had

MCL with a diffuse or nodular pattern or a blastoid

cytologic variant. Patients who had MCL with a pure

mantle zone pattern were excluded. Other eligibility

criteria included age older than 16 years (no upper

limit), good performance status (Zubrod score of 2 or

less),11 and adequate organ function, defined as car-

diac ejection fraction �50%, serum bilirubin level

<1.5 mg/dL, and serum creatinine level <2 mg/dL.

Moreover, the study required an absolute neutrophil

count (ANC) �1000/lL and a platelet count

�100,000/lL, unless a lower value was due to the

lymphoma. All patients had to agree to receive trans-

fusions of blood products as needed.

Patients were ineligible if they had central nerv-

ous system involvement, were infected with the

human immunodeficiency virus, were pregnant, had

comorbid physical or mental illness that precluded

treatment, or had a second malignancy that caused a

predicted chance of 5-year survival <90%.

Pretreatment Clinical EvaluationPretreatment evaluation included a physical exami-

nation; chest radiography; computed tomography

(CT) of the chest, abdomen, and pelvis; bilateral

bone marrow biopsy and aspiration; and an optional

gallium scan or positron emission tomography

(PET). In addition, blood was drawn for serum

chemistry analysis, a complete blood count with dif-

ferential analysis, measurement of serum b2-micro-

globulin, and flow cytometric analysis of lymphocyte

membrane-surface markers.

Pathologic AnalysisWe reviewed all pathologic materials and performed

fine-needle aspiration in recurrent, diseased, lymph

nodes to confirm the diagnosis and classification

using the World Health Organization system.12 All bi-

opsy specimens from which the original diagnosis

was made were reassessed for cyclin D1 expression

by sectioning of fixed, paraffin-embedded tissue.

Tests for other B-cell and T-cell markers, most com-

monly CD5 and CD20, were also performed. Bone

marrow and peripheral blood specimens were ana-

lyzed by flow cytometry. A classic polymerase chain

reaction technique was used to detect the presence

of t(11;14)(q13;q32), which involves the major trans-

location cluster for the bcl-1 locus, as previously

described.13 In addition, fluorescence in situ hybridi-

zation analysis was used to assess specimens for the

presence of the 11q13 and 11q14 break points.14 The

diagnosis of MCL in each patient in this study was

based on the presence of compatible morphologic

and immunophenotypic findings along with the

expression of cyclin D1 presence of t(11;14)(q13;q32).

Endoscopic biopsy specimens from affected sites in

the gastrointestinal tract were labeled and assessed

separately. For each patient in this study believed to

have gastrointestinal tract involvement of MCL, at

least 1 (usually 2 and rarely 3) biopsy specimen was

assessed immunohistochemically for the presence of

CD5, CD20, and cyclin D1 in fixed, paraffin-embed-

ded, tissue sections. For patients without lymph-

node biopsy specimens, we made tissue diagnosis by

examining gastrointestinal, bone marrow, or periph-

eral blood specimens.

ChemotherapyThe treatment scheme was as follows: Cycle 1 (ritux-

imab plus hyper-CVAD) was a 21-day cycle, adminis-

tered on either an outpatient or inpatient basis,

consisting of rituximab at a dose of 375 mg/m2 on

Day 1, followed by cyclophosphamide at a dose of

300 mg/m2 per dose given intravenously over 3 hours

every 12 hours for 6 doses on Days 2, 3, and 4.

Mesna was started 1 hour before the start of cyclo-

phosphamide, at a dose of 600 mg/m2 intravenously

and was given over 24 hours daily on Days 2, 3, and

Rituximab and Hyper-CVAD in Relapsed or Refractory MCL/Wang et al 2735

4, with the infusion completed 12 hours after admin-

istration of the last dose of cyclophosphamide.

Twelve hours after the last dose of cyclophospha-

mide, doxoribicin at a dose of 16.6 mg/m2 was given

by continuous intravenously infusion over 24 hours

daily on Days 5, 6, and 7. Vincristine at a dose of 1.4

mg/m2 (maximum absolute dose, 2 mg) was given

by intravenously infusion 12 hours after the last dose

of cyclophosphamide and was repeated on Day 12 of

the cycle. Dexamethasone at a 40-mg absolute dose

was given orally or intravenously on Days 2 to 5 and

12 to 15 of the cycle. Patients with evidence of pe-

ripheral blood involvement (as determined by flow

cytometric analysis at the time of initial presenta-

tion) may have had their first dose of rituximab

delayed or omitted at the discretion of the clinician

when they were believed to be at risk for tumor-lysis

syndrome or cytokine-release syndrome. Prophylaxis

for each course included granulocyte colony-stimu-

lating factor (G-CSF) at 5 lg/kg subcutaneously, vala-

cyclovir at 500 mg orally, fluconazole at 100 mg

orally, and ciprofloxacin at 500 mg orally twice a day,

all given daily for 10 days starting 24 to 36 hours af-

ter the end of the infusion of doxorubicin.

Cycle 2 (rituximab plus methotrexate-cytarabine)

was a 21-day cycle given on an inpatient basis and

consisted of rituximab at a dose of 375 mg/m2 on

Day 1, followed on Day 2 by methotrexate at a dose

of 200 mg/m2 administered intravenously over 2

hours and then methotrexate at a dose of 800 mg/m2

by constant intravenously over 22 hours. Before

methotrexate administration began, the patient’s

urine was alkalinized to a pH of 6.8 or higher and

kept at this level until the methotrexate was cleared

from the blood. For patients with an initial serum

creatinine level >1.5 mg/dL, the dose of methotrex-

ate was decreased by 50%. In patients with evidence

of third spacing of fluids, the fluid was tapped com-

pletely or, when this was not possible, rituximab plus

hyper-CVAD was repeated for the next cycle until the

third spacing resolved (this situation was rare). Cytar-

abine was given at 3000 mg/m2 per dose over 2

hours every 12 hours for 4 doses on Days 3 and 4 of

the cycle. The cytarabine dose was automatically

reduced to 1000 mg/m2 in patients older than 60

years and in those with a serum creatinine level >1.5

mg/dL. A 1% ophthalmic solution of prednisolone,

given at a rate of 2 drops in each eye 4 times daily,

was started on Day 3 at the start of cytarabine infu-

sion and was continued for 7 days to prevent chemi-

cal conjunctivitis. Folinic acid (citrovorum factor)

rescue therapy (50 mg) was given orally 12 hours af-

ter the infusion of methotrexate was completed, and

then 15 mg orally every 6 hours for 8 doses. Serum

methotrexate levels were checked at 24 and 48 hours

after the end of the infusion, and the dose of folinic

acid was increased to 100 mg intravenously every 3

hours when the serum level was either >1 lM (at 24

hours) or >0.1 lM (at 48 hours). Prophylaxis given

with Cycle 2 was otherwise similar to that given with

Cycle 1. The use of erythropoietin was permitted

throughout therapy.

Evaluation During and After TreatmentThe following tests were performed every 2 cycles:

CT of the chest, abdomen, and pelvis; gallium scan

or PET, and bilateral bone marrow biopsy with uni-

lateral aspiration. To confirm CR, esophagogastro-

duodenoscopy and colonoscopy were performed,

with biopsies performed randomly. Upon completion

of therapy, patients underwent the same studies

(except for gallium scan or PET and endoscopies) ev-

ery 3 months during the first year, every 4 months

during the second year, every 6 months during the

third and fourth years, and yearly thereafter.

Total Number of Chemotherapy CoursesPatients who achieved a CR after the first 2 cycles (1

rituximab plus hyper-CVAD and 1 rituximab plus

methotrexate with cytarabine) received 4 more

cycles, for a total of 6 cycles. Patients who achieved

a partial response (PR) after 2 cycles and a complete

remission after 6 cycles received 2 more cycles, for a

total of 8 cycles. Patients with evidence of disease

after 6 cycles were removed from the study. Patients

whose disease was responding could be referred at

any time during treatment for consolidation with

stem-cell transplantation.

Dose Adjustment due to ToxicityGrade 3 nonhematologic toxicity required a 1-dose-

level decrease of the offending drug.

Grade 4 nonhematologic toxicity was discussed

with the principal investigator on a case-by-case ba-

sis, with options ranging from dose level reduction to

the patient’s removal from the study. Grade 3 or 4

hematologic toxicity during the nadir of each cycle

did not require dose adjustments. Instead, doses of

myelotoxic drugs were adjusted according to the

patients’ blood counts on Day 21 of the cycle as fol-

lows: a platelet count between 75,000/lL and

100,000/lL, or an ANC between 750/lL and 1000/lLwarranted a delay in the treatment until the counts

recovered to >100,000 platelets/lL and >1000 ANC/

lL, without a decrease in the dose; however, when

the platelet count was <75,000/lL or the ANC was

<750/lL, then therapy was delayed until the platelet

count increased to 100,000/lL and the ANC to 1000/lL,

2736 CANCER November 15, 2008 / Volume 113 / Number 10

and the next similar regimen was administered at a

1-dose-level reduction of the myelotoxic drugs.

Response CriteriaResponse was assessed according to standard Inter-

national Workshop Criteria.15 Refractory disease was

defined as achievement of less than a partial

response or a persistent partial response or progres-

sion with additional cycles or appearance of a new

lesion during therapy. Treatment failure was defined

as recurrence or progression of disease, death due to

disease or toxic effects, or death due to treatment-

related second malignancies.

Statistical MethodsPatients who underwent consolidation therapy with

stem-cell transplantation were censored for the fail-

ure-free survival analysis. The Fisher exact test was

used to test for associations between CR and patient

characteristics. The Kaplan-Meier product-limit

method was used to estimate both failure-free sur-

vival and overall survival (OS).16 The log-rank test17

was used to test for differences in failure-free survival

and OS between groups of patients aggregated

according to several variables, age, presence or ab-

sence of bone marrow involvement, presence or

absence of any amount of peripheral blood involve-

ment (as judged by morphologic assessment only),

blastoid or other cytology, pretreatment serum levels

of b2-microglobulin and lactate dehydrogenase

(LDH), presence or absence of an enlarged spleen by

CT as judged by the radiologist, and International

Prognostic Index score for aggressive non-Hodgkin

lymphoma.18 A P < .05 was deemed statistically sig-

nificant. High b2-microglobulin level was defined as

a b2-microglobulin level �3 mg/L, and high LDH

was defined as an LDH level >upper normal range,

or 618 U/L. All tests were 2-sided. Patients who

underwent stem-cell transplantation were censored

at the time of transplant.

RESULTSThirty-one patients with relapsed or refractory MCL

were enrolled in this prospective trial. Two were lost

to follow-up, leaving 29 evaluable for response and

toxicity. The patients’ median age was 63 years

(range, 45-78 years), and the male:female ratio was

5:1.

Treatment HistoryTables 1 and 2 show prior therapies and response,

respectively. The median number of prior regimens

was 1 (range, 1-5 prior regimens). Most patients had

received a doxorubicin-containing regimen or a

rituximab-containing regimen. First-line therapies

were as follows: CHOP (cyclophosphamide, doxoribi-

cin, vincristine, prednisone) with or without rituxi-

mab or radiotherapy (17 patients); HyperCVAD or

MA (cyclophosphamide, vincristine, doxorubicin,

dexamethasone, methotrexate, cytarabine) alternat-

ing with stem-cell transplantation (1 patient);

HyperCVAD/MA with rituximab (2 patients); PRO-

MACE/CYTABOM (prednisone, doxorubicin, cyclo-

phosphamide, etoposide, cytarabine, bleomycin,

vincristine, methotrexate, folinic acid) followed by

stem-cell transplantation (1 patient); fludarabine and

cyclophosphamide (1 patient); fludarabine (1

patient); FND (fludarabine, mitoxantrone, dexameth-

asone) with rituximab (1 patient); CVP (rituximab,

cyclophosphamide, vincristine, prednisone) with or

without rituximab (3 patients); and rituximab fol-

lowed by bexxar (1 patient). Overall, including front-

line and subsequent therapies, 4 patients had

previously received rituximab plus hyper-CVAD alter-

nating with rituximab plus methotrexate-cytarabine,

and 5 patients had a disease relapse after undergoing

autologous stem-cell transplantation. Responses to

the previous treatment included CR in 10 (35%)

patients, PR in 7 (24%) patients, and no response or

progression in 12 (41%) patients.

TABLE 1Prior Therapies Used in 29 Patients With Relapsedor Refractory Mantle Cell Lymphoma

Therapy No. of Patients

Median prior no. of regimens (range) 1 (1-5)

Doxorubicin-containing regimens 21

Fludarabine-containing regimens 5

Rituximab-containing regimens 18

Radiotherapy (excluding TBI) 9

Zevalin or Bexxar 2

Rituximab plus hyperCVAD alternating

with rituximab plus methotrexate-cytarabine

4

Autologous stem cell transplantation or TBI 5

TBI indicates total body irradiation.

TABLE 2Responses to Prior Therapies Among 29 Patients With Relapsed orRefractory Mantle Cell Lymphoma

Response No. (%)

CR 10 (35)

PR 7 (24)

Less than PR 12 (41)

CR indicates complete response; PR, partial response.

Rituximab and Hyper-CVAD in Relapsed or Refractory MCL/Wang et al 2737

Response to Salvage Rituximab Plus Hyper-CVADAlternating With Rituximab Plus Methotrexate-CytarabineResults of this trial are summarized in Table 3. The

median number of cycles received was 5 (range, 1-7

cycles), with an overall response rate (ORR) of 93%

(45% CR or CR unconfirmed [CRu] and 48% PR). All

5 patients whose disease was resistant to the previ-

ous treatment experienced a response (1 CR, 4 PR),

and both patients whose disease did not change in

response to prior therapy also experienced a

response (2 PRs). We evaluated the 14 patients whose

current response was classified as PR and found that

in 4 of them, this was the best response ever

achieved; another 5 patients were referred for stem-

cell transplantation while the tumor was still

responding. Nine of 29 (31%) of the patients under-

went consolidation therapy with nonmyeloablative

stem-cell transplantation. Reasons for no transplan-

tation in order of frequency included age (7

patients), no insurance (3 patients), less than a par-

tial response (3 patients), patient refusal (3 patients),

and lack of compatible donor (2 patients). One

patient had a heart attack and another patient’s phy-

sician chose not to offer transplantation.

No pretreatment variable (number of prior

chemotherapy regimens, response to previous regi-

mens, pretreatment serum levels of b2-microglobulin

or LDH, or age) was associated with achievement of

a CR. There was no response or duration of response

difference by intensity of prior therapy received. Two

patients received radioimmunoconjugates as 1 of

their prior therapies; 1 patient tolerated well the cur-

rent regimen, and another patient developed delays

in therapy and infections but was able to proceed to

stem-cell transplantation.

ToxicityToxic effects of the chemotherapy are summarized in

Table 4. The principal toxic effects were hematologic.

In a total of 104 cycles of chemotherapy given, the

rates of grade 4 neutropenia and grade 4 thrombocy-

topenia were 60% and 54%, respectively. The inci-

dence of neutropenic fever was 11%, and there were

no deaths due to toxicity. In 4 cases, toxicity pre-

cluded continuation of therapy because of myelosup-

pression and associated neutropenic infections.

These were all patients older than 65 years of age.

The number of patients who did not undergo trans-

plantation and who could not finish the 6 cycles of

treatment were 4 of 20 (25%).

Failure-free Survival and Overall SurvivalWith a median follow-up interval of 40 months

(range, 4-58 months), the median failure-free survival

(FFS) time was 11 months and the median overall

(OS) time was 19 months. Neither the FFS nor the

OS curves reached plateau (Fig. 1). No pretreatment

variable (number of prior chemotherapy regimens,

response to the previous regimen, pretreatment

TABLE 3Response Rates Among 29 Patients With Relapsed or RefractoryMantle Cell Lymphoma

Response No. (%)

CR/CRu 13 (45)

PR 14 (48)

CR/CRu1PR 27 (93)

Failed 2 (7)

CR/Cru indicates complete response (CR) or CR unconfirmed (Cru); PR, partial response.

TABLE 4Toxicity Rates in 104 Cycles of Rituximab Plus Hyper-CVAD Alternat-ing With Rituximab Plus Methotrexate-Cytarabine Therapy

Toxicity grade 1 2 3 4

% % % %

Neutropenic fever 0 3 11 0

Neutropenia 6 6 14 60

Thrombocytopenia 21 15 9 54

Fatigue 36 6 0 0

Sensory loss 18 2 1 0

Nausea 17 21 0 0

Pruritus 15 3 2 0

Edema 13 18 0 0

Non-neutropenic fever 11 0 0 0

Diarrhea 10 6 0 0

Muscle weakness 10 0 0 0

Stomatitis 5 6 0 0

Constipation 4 11 0 0

Vomiting 4 10 0 0

FIGURE 1. Failure-free survival of 29 patients with relapsed or refractorymantle cell lymphoma treated with the present intense chemotherapy

regimen.

2738 CANCER November 15, 2008 / Volume 113 / Number 10

serum levels of b2-microglobulin or LDH, and age)

was associated with better FFS.

DISCUSSIONWe previously reported results of a treatment with a

novel combination of a monoclonal antibody and

intense chemotherapy, in which rituximab plus

hyper-CVAD was alternated with rituximab plus

methotrexate-cytarabine in newly diagnosed patients

with aggressive MCL.10 The rates of overall response

and complete response to this regimen, when admi-

nistered as first-line therapy, were 97% and 87%,

respectively, and at 3 years, the median failure-free

survival had not been reached. We, therefore,

decided to test this regimen in the more challenging

setting of relapsed or refractory MCL.

Patients accrued on the current trial showed an

excellent overall response rate of 93% and, more

importantly, a CR or CRu rate of 45%, thus poten-

tially making more patients eligible for consolidation

with stem-cell transplantation than was possible

when we used standard therapies.

Our sample of patients is representative of the

population of patients with relapsed MCL, in that

they previously received doxorubicin-containing

chemotherapy, mostly in combination with the

monoclonal antibody rituximab. Furthermore, 4

patients had previously received a similar intense

regimen, and 5 patients had disease relapse after

undergoing autologous stem-cell transplantation.

The finding that these patients responded to our reg-

imen supports the efficacy of the combination.

Other salvage therapies have resulted in CR rates

of 9% to 80% and PR rates of 21% to 80% (Table 5).

(It should be noted that the higher response rates

were obtained in studies with only 5 patients.) Com-

bining our intense regimen with other targeted thera-

pies that do not have overlapping toxic effects may

further improve outcomes, but this hypothesis

remains to be tested. The final treatment recommen-

dation for a patient with a recurrence will depend on

his or her potential for consolidation with stem-cell

transplantation and his or her performance status.

No variable predicted CR, possibly because of

the regimen’s effectiveness. However, our analysis of

response was confounded because a portion of the

patients with PR underwent stem-cell transplantation

while they were still responding to the regimen.

Assessment of the relation between pretreatment

prognostic variables and failure-free survival was

similarly limited.

Hematologic toxicity in the current study was

frequent, as is expected for a regimen of such inten-

sity, but only 11% of the cycles were associated with

neutropenic fever, and there were no deaths due to

toxicity. No patient has developed myelodysplasia or

acute leukemia, a complication that has been

reported in other trials with a similar regimen.10

TABLE 5Published Response Rates for Different Salvage Therapies for Relapsed or Refractory Mantle Cell Lymphoma

Author Regimen No. of Patients % CR % PR % ORR

Foran19 Rituximab 35 14 23 37

Gressin20 VAD�chlorambucil* 30 43 30 73

Kaufmann21 Rituximab1thalidomide 16 31 50 81

Dang22 Ontak 8 12.5 25 37.5

Cohen23 Cyclophosphamide1fludarabiney 30 30 33 63

Goy24 Bortezomib 29 21 21 42

O’Connor25 Bortezomib 11 9 36 45

McLaughlin26 Fludarabine1mitoxantrone1dexamethasone 5 20 80 100

Seymour27 Fludarabine1cisplatin1cytarabine 8 88

Forstpointner28 Fludarabine1cyclophosphamide1mitoxantrone 24 0 46 46

Forstpointner28 Fludarabine1cyclophosphamide1mitoxantrone1rituximab 24 29 29 58

Levine29 Fludarabine1mitoxantrone1rituximab 5 80 0 80

Rummel30 Bendamustine1rituximab 16 50 25 75

Fisher31 Bortezomib 141 8 25 33

Robak32 2-CdA1rituximab or rituximab with cyclophosphamide 9 22 45 67

Rupolo33 Rituximab1oxaliplatin1cytarabine 9 NA NA 100

Drach34 Rituximab1bortezomib1dexamethasone 12 25 50 75

CR indicates complete response; PR, partial response; ORR, overall response rate; VAD, vincristine, doxorubicin, dexamethasone; NA, not available.

*30% untreated.y33% untreated.

Rituximab and Hyper-CVAD in Relapsed or Refractory MCL/Wang et al 2739

The high response rates achieved with rituximab

plus hyper-CVAD alternating with rituximab plus meth-

otrexate-cytarabine in patients with relapsed or refrac-

tory MCL lead us to conclude that this regimen is an

option for induction therapy before stem-cell trans-

plantation. The data also suggest that this regimen will

improve rates of long-term survival in such patients.

REFERENCES1. Meusers P, Engelhard M, Bartels H, et al. Multicentre ran-

domized therapeutic trial for advanced centrocytic lym-

phoma: anthracycline does not improve the prognosis.

Hematol Oncol. 1989;7:365-380.

2. Norton AJ, Mathews J, Pappa V, et al. Mantle cell lym-

phoma: natural history defined in a serially biopsied popu-

lation over a 20 year period. Ann Oncol. 1995;6:249-256.

3. Argatoff LH, Connors JM, Klasa RJ, et al. Mantle cell lym-

phoma: a clinicopathologic study of 80 cases. Blood. 1997;

89:2067-2078.

4. Teodorovic I, Pittaluga S, Kluinnelemans JC, et al. Efficacy

of 4 different regimens in 64 mantle cell lymphoma cases.

Clinicopathologic comparison with 498 other non-Hodg-

kin’s lymphoma subtypes. J Clin Oncol. 1995;13:2819-2826.

5. Zucca E, Roggero E, Pinotti G, et al. Patterns of survival in

mantle cell lymphomas. Ann Oncol. 1995;6:257-282.

6. Fisher RI, Dahlberg S, Nathwani BN, et al. A clinical analy-

sis of 2 indolent lymphoma entities: mantle cell lymphoma

and marginal zone lymphoma (including mucosa-asso-

ciated lymphoid tissue and monocytoid B-cell categories).

a Southwest Oncology Group study. Blood. 1995;85:1075-

1084.

7. Greiner TC, Moynihan MJ, Chan WC, et al. P53 mutations

in mantle cell lymphoma are associated with variant cytol-

ogy and predict a poor prognosis. Blood. 1996;87:4302-4310.

8. Khouri IF, Romaguera J, Kantarjian H, et al. Hyper-CVAD

and high-dose methotrexate/cytarabine followed by stem

cell transplantation: an active regimen for aggressive man-

tle cell lymphoma. J Clin Oncol. 1998;16:3803-3809.

9. Khouri IF, Lee MS, Saliba R, et al. Non-ablative allogeneic

stem cell transplantation for advanced/recurrent mantle

cell lymphoma. J Clin Oncol. 2003;21:4407-4412.

10. 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;23:7013-

7023.

11. Stanley KE. Prognostic factors for survival in patients with

inoperative lung cancer. J Natl Cancer Inst. 1980;65:25-32.

12. Harris NL, Jaffe ES, Diebold J, et al. The World Health Or-

ganization classification of neoplastic diseases of the hae-

matopoietic and lymphoid tissues: Report of the Clinical

Advisory Committee Meeting, Airlie House, Virginia, No-

vember 1997. Histopathology. 2000;36:69-86.

13. Luthra R, Sarris AH, Hai S, et al. Real-time 50->30 exonucle-ase-based PCR assay for detection of the t(11;14)(q13;q32).

Am J Clin Pathol. 1999;112:524-530.

14. Katz RL, Caraway NP, Gu J, et al. Detection of chromosome

11q13 breakpoints by interphase fluorescence in situ hybri-

dization. A useful ancillary method for the diagnosis of

mantle cell lymphoma. Am J Clin Pathol. 2000;114:248-

257.

15. Cheson BD, Horning SJ, Coiffier B, et al. Report on an

international workshop to standardize response criteria for

non-Hodgkin’s lymphomas. NCI Sponsored International

Working Group. J Clin Oncol. 1999;10:1244-1253.

16. Kaplan EL, Meier P. Nonparametric estimation from

incomplete observations. J Am Stat Assoc. 1958;53:457-481.

17. Peto R, Peto J. Asymptotically efficient rank invariant test

procedures. J Roy Stat Soc. 1972;135:185-207.

18. Shipp MA; Harrington DP, and the International Non-

Hodgkin’s Lymphoma Prognostic Factors Project, et al. A

predictive model for aggressive non-Hodgkin’s lymphoma.

N Engl J Med. 1993;329:987-994.

19. Foran JM, Rohatiner AZ, Cunningham D, et al. Europeanphase 2 study of rituximab (chimeric anti-CD20 monoclo-

nal antibody) for patients with newly diagnosed mantle-

cell lymphoma and previously treated mantle-cell lym-

phoma, immunocytoma, and small B-cell lymphocytic

lymphoma. J Clin Oncol. 2000;18:317-324.

20. Gressin R, Legouffe E, Leroux D, et al. Treatment of man-

tle-cell lymphomas with the VAD � chlorambucil regimen

with or without subsequent high-dose therapy and periph-

eral blood stem-cell transplantation. Ann Oncol. 1997;

8(suppl 1):103-106S.

21. Kaufmann YL, Jones RJ, Diehl LF, et al. Antitumor activity of

rituximab plus thalidomide in patients with relapsed or re-

fractory mantle cell lymphoma. Blood. 2004;104:2269-2271.

22. Dang NH, Hagemeister FB, Pro B, et al. Phase 2 study of

denileukin diftitox for relapsed or refractory B-cell non-

Hodgkin’s lymphoma. J Clin Oncol. 2004;22:4095-4102.

23. Cohen BJ, Moskowitz C, Strauss D, et al. Cyclophospha-

mide/fludarabine (CF) is active in the treatment of mantle

cell lymphoma. Leuk Lymphoma. 2001;42:1015-1022.

24. Goy A, Younes A, McLaughlin P, et al. Phase 2 study of pro-

teasome inhibitor bortezomib in relapsed or refractory B-

cell non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23:667-

675.

25. O’Connor OA, Wright J, Moskowitz C, et al. Phase 2 clinical

experience with the novel proteasome inhibitor bortezomib

in patients with indolent non-Hodgkin’s lymphoma and

mantle cell lymphoma. J Clin Oncol. 2005;23:676-684.

26. Mclaughlin P, Hagemeister FB, Romaguera JE, et al. Fludar-

abine, mitoxantrone, and dexamethasone: an effective new

regimen for indolent lymphoma. J Clin Oncol. 1996.;14:

1262-1268.

27. Seymour JF, Grigg AP, Szer J, Fox RM. Fludarabine and

mitoxantrone: effective and well-tolerated salvage therapy

in relapsed indolent lymphoproliferative disorders. Ann

Oncol. 2001;12:1455-1460.

28. Forstpointner R, Dreyling M, Repp R, et al. The addition

of rituximab to a combination of fludarabine, cy-

clophosphamide, mitoxantrone (FCM) significantly in-

creases the response rate and prolongs survival as

compared with FCM alone in patients with relapsed and

refractory follicular and mantle cell lymphomas: results

of a prospective randomized study of the German Low-

Grade Lymphoma Study Group. Blood. 2004;104:3064-

3071.

29. Levine AM, Espina BM, Mohrbacher LH, et al. Fludarabine,

mitoxantrone, and rituxan: an effective regimen for the

treatment of mantle cell lymphoma [abstract]. Blood.

2002;100(suppl 1):361A.

30. Mathias J. Rummel, Al-Batran SE, Kim SZ, et al. Bendamus-

tine plus rituximab is effective and has a favorable toxicity

profile in the treatment of mantle cell and low-grade non-

Hodgkin’s lymphoma. J Clin Oncol. 2005;23: 3383-3389.

2740 CANCER November 15, 2008 / Volume 113 / Number 10

31. Fisher RI, Bernstein SH, Kahk BS, et al. Multicenter phase

2 study of bortezomib in patients with relapsed or refrac-

tory mantle cell lymphoma. J Clin Oncol. 2006.;24:4867-

4874.

32. Robak T, Smolewski P, Sebula B, et al. Rituximab combined

with cladribine or with cladribina and cyclophosphamide

in heavily pretreated patients with indolent lymphoproli-

ferative disorders and mantle cell lymphoma. Cancer.

2006;107:1542-1550.

33. Rupolo M, Michieli M, Spina M, et al. R-Dhaox, high dose

chemotherapy (HDC) and rituximab maintenance as sal-

vage treatment in relapsed or refractory (R/R) follicular (F)

and mantle cell (MC) lymphomas (NHL) [abstract]. J Clin

Oncol. 2007:100(suppl 18):450S. (Abstract 8036).

34. Drach J, Kaufmann H, Pichelmayer O, et al. Marked activity

of bortezomib, rituximab and dexamethasone in relapsed

and refractory mantle cell lymphoma [abstract]. Blood.

2006;108:779A.

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