BVR in relaspsed NHL, mixed histology

[Guest guest]

924 Bendamustine, Bortezomib and Rituximab in Patients (pts)

Relapsed/Refractory Indolent and Mantle Cell Non-Hodgkin

Lymphoma (NHL): a Multicenter Phase II Clinical Trial

n = 31, median 4 prior treatment, 33% rituxan refractory. 50%

CR/CRu rate.

http://ash.confex.com/ash/2009/webprogram/Paper18182.html

Oral and Poster Abstracts

Oral Session: Lymphoma: Chemotherapy, excluding Pre-Clinical

Models - New Treatments

Tuesday, December 8, 2009: 8:45 AM

260-262 (Ernest N. Morial Convention Center)

W. Friedberg, MD1, M. Vose, M.D.2, L

, PhD, MPH3, Faith Young, MD4*, Jane Liesveld, MD3*,

O. Armitage, M.D.5*, Proia, MPH1*, Kim Cruttenden, N.P.1*

and P. Leonard, MD6

1 P. Wilmot Cancer Center, University of Rochester,

Rochester, NY

2Internal Medicine Section of Hematology/Oncology, University of

Nebraska Medical Center, Omaha, NE

3University of Rochester, Rochester, NY

4Cancer Center, University of Rochester Medical Center,

Rochester, NY

5Pathology and Microbiology, University of Nebraska Medical

Center, Omaha, NE

6Department of Hematology/Oncology, Weill Cornell Medical

College, New York, NY

Bendamustine ( is an alkylating agent recently approved for

relapsed and refractory indolent non-Hodgkin lymphoma NHL. In

vitro studies suggest synergy between bendamustine and rituximab

®, and two phase II trials of this combination demonstrated

tolerability and high response rates in indolent and mantle cell

(MCL) NHL.

The proteasome inhibitor bortezomib (Velcade; V) has significant

single agent activity in indolent and mantle cell NHL. We have

completed enrollment of a multicenter phase II trial combining

bortezomib with the bendamustine/rituximab combination.

Eligible pts had relapsed or refractory indolent or mantle cell

NHL.

Treatment consisted of B 90 mg/m2 day 1 and 4; R 375 mg/m2 day 1

and V 1.3 mg/m2 day 1, 4, 8, 11. Six 28-day cycles of therapy

were planned. 31 patients (23 male) were enrolled; median age

was 64 yrs (range 44-84).

Histology included 16 follicular NHL, 7 MCL, 3 marginal zone

NHL, 3 SLL and 2 lymphoplasmacytic NHL.

Patients were heavily pretreated with a median of 4 prior

regimens, including anthracycline containing chemotherapy

(n=19), purine analog chemotherapy (n=6), ASCT (n=6), and

radioimmunotherapy (n=9). 10 pts were refractory to rituximab

and 25 pts had advanced stage disease at time of study.

One pt never received therapy due to transformation. One pt

died of sepsis after the first cycle of therapy. Common

expected toxicities included thrombocytopenia, fatigue, fever,

anemia, neutropenia and infusion reactions. Peripheral

neuropathy was reported in 18 pts, including 2 with grade 3

neurotoxicity; additionally 14 patients reported constipation.

There were 5 pts who developed varicella zoster reactivation (no

prophylaxis given). Fourteen pts completed 6 cycles; reasons

for premature withdrawal include progressive disease (PD),

(n=4); cytopenias (n=4), infection (n=2), death (n=1) and nausea

(n=1); 4 patients currently remain on treatment as of August

2009. Of 25 pts evaluable for response, overall response rate

was 84% (95%CI 65%-94%). Best response following therapy was

CR/Cru: 13 (52%); PR: 8 (32%); SD: 1(4%); PD: 3 (12%).

Interestingly, 11/11 pts with FL responded to treatment

(including 7 (64%) CR/CRu), and 5/7 pts with MCL responded to

treatment.

With a median follow-up of 13 months, 4 patients have died (3 of

PD). There is no association between prior ASCT,

radioimmunotherapy or purine analog chemotherapy and premature

study withdrawal.

There was also no association between rituximab sensitivity and

response to BVR.

Correlative laboratory studies are ongoing to determine

predictors of toxicity and response.

In summary, in this heavily pretreated population (as compared

with prior studies of BR, including 33% rituximab-refractory

pts), the BVR regimen is highly active, with over half of

evaluable pts achieving CR/CRu.

It appears more toxic than BR alone, with expected additive

toxicities from V. Prophylaxis against varicella zoster

reactivation is indicated when using this regimen. Further

follow-up will determine whether the high CR/CRu rate

corresponds to prolonged PFS. These promising results warrant

additional evaluation of this regimen in de novo disease.

Ultimately, a randomized trial will be necessary to determine

the degree to which V adds efficacy to the BR combination.

Disclosures: Friedberg: cephalon: Research Funding; millenium:

Research Funding; genentech: LymphoCare Advisory Board. Off

Label Use: bendamustine/bortezomib/rituximab combination

therapy.