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A Randomized Phase II Trial of R-HCVAD/MTX/ARA-C Induction Followed by Consolidation With an Autologous Stem Cell Transplant Vs. R-Bendamustine Induction Followed by Consolidation With an Autologous Stem Cell Transplant for Patients ≤ 65 Years of Age With Previously Untreated Mantle Cell Lymphoma

Phase 2
18 Years
65 Years
Open (Enrolling)

Thank you

Trial Information

A Randomized Phase II Trial of R-HCVAD/MTX/ARA-C Induction Followed by Consolidation With an Autologous Stem Cell Transplant Vs. R-Bendamustine Induction Followed by Consolidation With an Autologous Stem Cell Transplant for Patients ≤ 65 Years of Age With Previously Untreated Mantle Cell Lymphoma


- To estimate the 2-year progression-free survival (PFS) of patients with newly diagnosed
mantle cell lymphoma (MCL) treated with rituximab, cyclophosphamide, doxorubicin
hydrochloride, vincristine sulfate, dexamethasone (RHCVAD), methotrexate and cytarabine
(MTX/Ara-C), and autologous stem cell transplant (ASCT) or rituximab and bendamustine
(R-bendamustine) and autologous stem cell transplant and to select a regimen for
further development.

- To assess the response rate and overall survival of patients with newly diagnosed MCL
treated with R-HCVAD/MTX/Ara-C and ASCT or R-bendamustine and ASCT.

- To assess the toxicity and tolerability of R-HCVAD/MTX/Ara-C and ASCT or R-bendamustine
and ASCT in patients with newly diagnosed MCL.

- To determine the prognostic value of quantitative minimal-residual disease (MRD)
monitoring in the peripheral blood of MCL patients after induction therapy and serially
after high-dose chemotherapy and ASCT on treatment outcome.

- To bank diagnostic tissue sections for future translational research studies.

OUTLINE: This is a multicenter study. Patients are stratified according to risk
classification by Mantle Cell Lymphoma International prognostic Index (MIPI) score (low risk
vs intermediate/high risk). Patients are randomized to 1 of 2 treatment arms.

- Arm I (induction therapy):

- Courses 1 and 3: Patients receive induction therapy comprising rituximab IV on day
1; cyclophosphamide IV over 3 hours every 12 hours on days 2-4; doxorubicin
hydrochloride IV over 72 hours on days 5-7; vincristine sulfate IV on days 5 and
12; and dexamethasone IV or orally (PO) once daily (QD) on days 2-5 and 12-15.
Patients with responsive disease after course 1 proceed to course 2.

- Course 2 and 4: Patients receive rituximab IV on day 1; methotrexate IV over 2-22
hours on day 2; cytarabine IV over 2 hours every 12 hours on days 3-4; and
leucovorin calcium PO or IV on days 3-6. Patients undergo stem cell collection
after completion of course 2.

- Each course is 21 days long and continues in the absence of disease progression or
unacceptable toxicity.

- Arm II (induction therapy):

- Course 1-6: Patients receive rituximab IV on day 1 and bendamustine hydrochloride
IV over 30 minutes on days 1-2. Treatment repeats every 28 days for 4 courses in
the absence of disease progression or unacceptable toxicity. Beginning 3-4 weeks
later, patients with responsive disease receive 2 additional courses of treatment.

- Stem cell mobilization: Beginning within 8 weeks, patients receive rituximab IV
and cyclophosphamide IV over 1 hour on day 1. Patients then undergo stem cell
collection about 26 days later.

Consolidation therapy: Patients receive one of the following preparative regimens.

- BCV* chemotherapy: Carmustine IV over 2 hours on days -6 to -4; etoposide IV over 4
hours on day -4; and cyclophosphamide IV over 1 hour on day -2.

- BEAM* chemotherapy: Carmustine IV over 4 hours on days -7 and -6; etoposide IV over 1
hour twice daily and cytarabine IV over 2 hours twice daily on days -5 to -2, and
melphalan IV on day -1.

- TBI, etoposide, cyclophosphamide: Patients undergo total-body irradiation (TBI)** twice
daily on days -8 to -5. Patients also receive etoposide IV on day -4 and
cyclophosphamide IV over 1 hour on day -2.

- NOTE: * Patients 61 years of age or older receive either BCV or BEAM.

- NOTE: * *TBI may not be used for patients 61 years of age and older. Stem cell
transplantation: Patients then undergo autologous peripheral blood stem cell
transplantation on day 0.

After completion of study treatment, patients are followed up every 3 months for 1 year,
every 6 months for 2 years, and then annually for up to 8 years from registration.

Inclusion Criteria


- All patients must have previously untreated stage III, IV, or bulky stage II mantle
cell lymphoma (MCL)

- A diagnosis of MCL must be confirmed by histopathological diagnosis including
immunohistochemistry and flow cytometry documenting both of the following

- CD19+ or CD20+

- Cyclin D1+ or evidence of the t(11;14) translocation by cytogenetics or

- Adequate sections from the original diagnostic specimen must be available for
submission for central review

- An adequate biopsy requires sufficient tissue to establish the architecture and
a WHO histologic subtype with certainty

- Core biopsies, especially multiple core biopsies, MAY be adequate, but
needle aspirations or cytologies are not adequate

- Bone marrow core biopsy or clot sections (not aspirates) may be used as
diagnostic material if it is significantly involved and are the only diagnostic
material available

- All patients must have bidimensional measurable disease documented on the Lymphoma
Baseline Tumor Assessment Form (Form #48031)

- Patients who also have non-measurable disease in addition to measurable disease
must have all nonmeasurable disease assessed within 28 days prior to

- Patients must not have clinical evidence of central nervous system (CNS) involvement
by lymphoma

- Any laboratory or radiographic tests performed prior to registration to assess
CNS involvement must be negative

- Patients must have a unilateral/bilateral bone marrow aspirate and biopsy for staging
performed within 42 days prior to registration

- If the biopsy cannot be performed but the aspirate is unequivocally consistent
with mantle cell lymphoma, this will be considered adequate for staging purposes

- Patients must be eligible for stem cell transplantation by institutional guidelines
with the plan that transplant will be conducted at a cooperative group-approved
transplant center

- Patients must be planning to undergo stem cell transplantation within 84 days
after day 1 of the last induction course

- Patients must have had at least 1.5 X 10^6 CD34^+ cells/kg collected and stored
prior to second registration for stem cell transplantation


- Zubrod performance status of 0-2

- Bilirubin ≤ 3 times upper limit of normal (ULN)

- Serum creatinine ≤ 2.0 times ULN

- ALT and AST ≤ 2.5 times ULN

- Alkaline phosphatase ≤ 2.5 times ULN

- Platelet count ≥ 100,000/mcL, unless due to bone marrow infiltration by lymphoma

- All patients ≥ 45 years of age must have an echocardiogram (ECHO) or MUGA scan within
42 days prior to registration (whichever method is used at baseline must be used at

- Patients < 45 years of age should have ECHO/MUGA only if clinically indicated

- Patients with an ejection fraction < institutional lower limit of normal (ILLN)
are not eligible

- Serum LDH and a CBC with differential must be measured within 28 days prior to

- Patients known to be HIV positive, or who have a history of solid organ
transplantation, are ineligible

- No active hepatitis

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer; in situ cervical cancer; adequately treated
Stage I or II cancer from which the patient is currently in complete remission; or
any other cancer from which the patient has been disease-free for 5 years

- Pregnant or nursing women may not participate

- Women or men of reproductive potential may not participate unless they have agreed to
use an effective contraceptive method


- See Disease Characteristics

Type of Study:


Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

PFS at 2 years

Safety Issue:


Principal Investigator

Steven H. Bernstein, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

James P. Wilmot Cancer Center



Study ID:




Start Date:

November 2011

Completion Date:

Related Keywords:

  • Lymphoma
  • contiguous stage II mantle cell lymphoma
  • noncontiguous stage II mantle cell lymphoma
  • stage III mantle cell lymphoma
  • stage IV mantle cell lymphoma
  • Lymphoma
  • Lymphoma, Mantle-Cell



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