Flavopiridol, Fludarabine and Rituximab (FFR) for NHL/CLL

[Guest guest]

Greeting,

I'm not confortable with this study design. Apparently one purpose is to

see if this combination is feasible - can be given together without undue

risk to the participants. => " Fifteen pts were enrolled in cohort 1 and 14

pts were enrolled in cohort 4, to better define toxicity and efficacy. "

- But why include 22 previously untreated patients (more than 50%) in a

dose / toxicity finding study, which is the best opportunity to achieve a

durable remission?

Thankfully, for the participants, the results appear good so far, but

lacking a control group we can't know how it compares to other protocols in

the same setting (untreated/treated, MCL, FL, MZL ...) because N for each

subtype is so small (and even smaller for previously treated / untreated).

I suppose it could be argued that Fludarabine + Rituxan is a reasonable

first line therapy for each of these lymphoma subtypes, and they felt

comfortable with the toxicity profile of Flavopiridol ... if so, perhaps FR

will be the control if the remissions prove durable for FFR with follow up.

~ Karl

==

Flavopiridol, Fludarabine and Rituximab (FFR): An Active Regimen in Indolent

B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma

n = Thirty-eight pts, median age was 62 years (range, 38-81), CLL (11), MCL

(10), follicular (FL, 9), small lymphocytic (3), marginal zone (4) or

lymphoplasmacytic lymphoma (1). Sixteen pts had received 1 or 2 prior

therapies; 22 pts were previously untreated.

http://ash.confex.com/ash/2008/webprogram/Paper11147.html

Saturday, December 6, 2008, 5:30 PM-7:30 PM

Background: The cyclin-dependent kinase inhibitor flavopiridol (alvocidib)

induces p53-independent apoptosis and may be able to eliminate tumor cells

resistant to fludarabine and rituximab.

Study Design and Treatment:

We report final results of a phase I dose escalation study of flavopiridol

in combination with fludarabine and rituximab (FFR) in patients (pts) with

mantle cell lymphoma (MCL), indolent B-cell non-Hodgkin's lymphoma (B-NHL)

and chronic lymphocytic leukemia (CLL).

Pts had ANC ³ 1500, hemoglobin ³ 9.0, platelets ³ 100,000, adequate organ

function, and ECOG performance status 0-2, and provided informed consent.

Pts received fludarabine 25 mg/m2 IV on day 1-5 and rituximab 375 mg/m2 on

day 1 every 28 days for up to 6 cycles. Flavopiridol was administered 50

mg/m2 by 1-hr IV bolus on day 1 (cohort 1, n=15) or day 1 and 2 (cohort 2,

n=6) of each cycle.

Based on promising results with a novel single agent dosing schedule in CLL,

the study was amended to give flavopiridol by 30-min IV bolus followed by

4-hr IV infusion at a dose of 20 mg/m2 + 20 mg/m2 (cohort 3, n=3) or 30

mg/m2 + 30 mg/m2 (cohort 4, n=14) beginning with cycle 2. Pts were placed

on prophylactic Bactrim and Valtrex. Growth factor support was allowed in

cohorts 3 and 4.

Results:

Thirty-eight pts were enrolled. Median age was 62 years (range, 38-81), and

22 pts were male (58%). Pts had CLL (11), MCL (10), follicular (FL, 9),

small lymphocytic (3), marginal zone (4) or lymphoplasmacytic lymphoma (1).

Sixteen pts had received 1 or 2 prior therapies; 22 pts were previously

untreated.

Two of 6 pts in cohort 2 developed dose limiting toxicity; 1 pt developed

grade 3 confusion and grade 3 seizures, and 1 pt developed nausea and

diarrhea resulting in grade 3 acute renal failure. Fifteen pts were

enrolled in cohort 1 and 14 pts were enrolled in cohort 4, to better define

toxicity and efficacy.

Pts received a median of 4 cycles (range 1-6), and 16 of 38 pts completed

all 6 planned cycles. Cytopenias (10), fatigue (3), fever (2) and

progression (2) were the most common reasons for early discontinuation of

therapy. Response was graded by NCI 96 criteria (CLL) or IWG criteria

(NHL).

Overall response rate (ORR) was 82% (CR 50%, CRu 5%, PR 26%). Median

progression-free survival (PFS) of responders was 25.5 months. ORR (82% vs.

81%), CR (50% vs. 50%) and median PFS (25.7 vs. 25.1 months) were similar

for previously untreated and relapsed pts.

Thirteen pts remain in remission with a median PFS of 33.5 months (range,

17.5-59.5), and 3 other pts died of unrelated causes.

Eight of 10 MCL pts (median age 68, range 62-81) responded (7 CR, 1 PR).

Two responders with blastoid variant MCL relapsed within 1 year, but median

PFS of the other 6 responding MCL pts was 33.5 months.

All 9 FL pts responded (5 CR, 2 CRu, 2 PR) with a median PFS of 25.1 months

(range, 4.0-46.3).

Conclusions: FFR exhibited significant clinical activity in indolent B-NHL,

MCL and CLL. FFR was effective in both relapsed and previously untreated

pts and showed promising clinical activity in older MCL pts. Changing from

1-hr IV bolus dosing to 30-min IV bolus followed by 4-hr IV infusion did not

improve the response rate, suggesting that 1-hr IV bolus dosing may be

effective when flavopiridol is given as part of combination chemotherapy.

This regimen warrants further study.

Acknowledgements: This project was supported by National Cancer Institute

grants U01-CA76576 (to MRG) and K23 CA102276-01A1 (to TSL).

Hall A (Moscone Center)

Poster Board I-676

S. Lin, MD, PhD, Beth Fischer, BSN, RN*, Kristie A. Blum, MD,

Pierluigi Porcu, MD*, H. Kraut, MD, A. Baiocchi, MD, PhD, Mollie

E. Moran, MSN, CNP*, *, R. Grever, MD and C.

Byrd, MD

Division of Hematology and Oncology, The Ohio State University, Columbus, OH