Flavopiridol, Fludarabine and Rituximab (FFR)

[Guest guest]

I think this combination is of interest because of the potential of Flavopiridol

to overcome treatment resistence due to an inactive p53 pathway as describe in

this very technical article

http://www.nature.com/cdd/journal/v8/n11/full/4400918a.html

(In English, p53 is a gene that activates cell death in response to cell injury

from treatment. In some tumors this pathway to cell death is not working,

leading to drug resistence)

The mixed histologies (types of lymphomas) and treatment histories (some

previously untreated) likely make the results impossible to intrepret in many

respects. Probably the study was done to see if this combination could be

administered safely and to see if it was active.

- It's active alright, but is it more active than FR (fludarabine than Rituxan)?

Does it overcome refractory disease - the main rationale for including

Flavopiridol ... I think these questions would require a larger head to head

study.

~ Karl

==

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

B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma

Saturday, December 6, 2008

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

n = 38 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.

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).

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