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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: [email protected]
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.
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