NCCN_Campath_2010_Genzyme
- 1. May 10, 2010 Submission Request c/o NCCN NHL Panel Members National Comprehensive Cancer Network 275 Commerce Dr, Suite 300 Fort Washington, PA 19034 RE: Request for NCCN Guidelines Panel on NHL regarding Campath ® (alemtuzumab) in CLL with del(17p) Stanislav Lechpammer, MD, PhD Medical Director Genzyme Corporation 55 Cambridge Parkway, Cambridge, MA USA 02142 Phone: 617-591-5966 Email: stan.lechpammer@genzyme.com Dear NCCN NHL Panel Members, We respectfully request that the NCCN NHL panel consider the following changes to the Practice Guidelines for CLL with del(17p) with >20% cells: 1. Consider adding Campath ® (alemtuzumab) monotherapy as a treatment option for patients with relapsed/refractory CLL with del(17p) in >20% of cells 2. Consider re-evaluating order of alemtuzumab on the list of suggested treatment regimens in patients with first-line CLL with del(17p) in >20% of cells based on current clinical data The clinical rationale for these requests is summarized below. Request to add alemtuzumab monotherapy as a treatment option for patients with relapsed/refractory CLL with del(17p) in >20% of cells Five studies document the response of relapsed/refractory (R/R) CLL patients with del(17p) to alemtuzumab monotherapy (Table 1) 1,2,3,4,5 . The body of evidence supporting these regimens is similar if not greater than the evidence supporting some of the regimens recommended in the current NCCN guidelines for CLL (Table 2) 7,8,9,10,11 . The largest prospective study is described in greater detail below. In a multicenter, prospective, CLL2H study of the German Chronic Lymphocytic Leukemia Study Group (GCLLSG), responses were documented in del(17p) patients with fludarabine-refractory CLL receiving alemtuzumab monotherapy 1 . After dose escalation, patients received 30 mg of s.c. Campath three times a week for up to 12 weeks. 31 of the 103 evaluable patients had del(17p). In patients with del(17p), the observed ORR was 39%, median OS was 18.3%, median PFS was 5.8 months and median TTTF was 5.8 months. These results were statistically indistinguishable from patients with normal 17p status. Grades 3 to 4 neutropenia, thrombocytopenia, and anemia occurred in 56%, 57%, and 49% of patients, respectively. Grades 3 to 4 infections occurred in 29% and 8% of patients, respectively. All cytomegalovirus (CMV) episodes were successfully treated with anti-CMV therapy, and there were no CMV-related deaths. The authors concluded that “in contrast to chemotherapy-based therapy, alemtuzumab treatment overcomes the adverse prognostic impact of VH mutation status, TP53 mutation, and genomic aberrations.” Table 1. Alemtuzumab in R/R CLL with del (17p) Regimen No. Patients with del(17p) ORR CR PFS (Months) OS (Months) Reference 31 39% 0% 6 18 Stilgenbauer S, et al. J Clin Oncol. 2009;27:3994-4001. 46 44% 0% 7 19 Fiegl M, et al. Blood. 2008;112. Abstract 3164. 15 40% 0% - - Lozanski G, et al. Blood. 2004;103:3278-3281. 10 60% 0% - - Cortelezzi A, et al. Leukemia. 2009;Epub. 8 50% 0% - - Osuji NC, et al. Haematologica. 2005;90:1435-1436. Total: 110 39-60% Alemtuzumab
- 2. Table 2. Current Relapsed/Refractory Therapies as Listed in v.1.2010 NCCN Guidelines for CLL/SLL Regimen No. Patients with del(17p) ORR CR PFS OS References Currently Listed in NCCN Practice Guidelines for CLL CHOP+R - - - - - No reference listed (Leporrier study does not include subset analysis for 17p deletion) CFAR - - - - - No reference listed (Wierda study is frontline only) HyperCVAD+R - - - - - No reference listed OFAR 14 33% 7% 36% 6- month failure-free survival 86% 6-month survival Tsimberidou AM, et al. J Clin Oncol. 2008;26(2):196-203. 17 fludarabine + alemtuzumab- refractory 41% 0% - - Wierda WG, et al. J Clin Oncol 2009. 2010;28(10):1749-1755. Coiffier B, et al. Blood. 2008;111:1094-1100. 14 fludarabine- refractory bulky disease 14% 0% - - Wierda WG, et al. J Clin Oncol. 2010. 28(10):1749-1755. Coiffier B, et al. Blood. 2008;111:1094-1100. Alemtuzumab + rituximab 10 50% 10% 20.5 months No reference listed, but data are available from: Badoux X, et al. Blood. 2009;14. Abstract 1248, and a poster by Badoux X, et al. presented at ASH 2009. HDMP 10 50% 0% 8 months 20 months Thornton PD, et al. Ann Hematol. 2003; 82:759-765. Bendamustine 0 - - - - No reference listed; there are no published studies of bendamustine monotherapy in 17p deletion Total: 65 14-50% Ofatumumab Request to re-evaluate order of alemtuzumab on the list of suggested treatment regimens in patients with first-line CLL with del(17p) in >20% of cells based on current clinical data Efficacy data for alemtuzumab and other suggested treatment regimens for first-line patients with del(17p) are summarized in Table 3 6,12,13,14,15,16 . In a randomized, multicenter phase III trial comparing alemtuzumab to chlorambucil in front-line CLL 6 , 11 patients were found to have del(17p) upon study entry. 7 out of 11 (64%) patients responded, including 3 (27%) who achieved complete responses. Adverse events profiles were similar between the two arms, except for more infusion-related and CMV events with alemtuzumab and more nausea and vomiting with chlorambucil. CMV events had no apparent impact on efficacy. Table 3. Current First-Line Therapies as Listed in v.1.2010 NCCN Guidelines for CLL/SLL Regimen No. Patients with del(17p) ORR CR PFS (Months) OS (Months) Relevant References FCR 30* 74% 11% 15** 52 Zenz T, et al. Blood. 2009;114. Abstract 1267 29 76% 48% - - Tam C, et al. J Clin Oncol. 2008; 26. Abstract 7035. 3 - 0% 20*** - Byrd J, et al. J Clin Oncol. 2006; 24:437-443. HDMP + R 1 100% 0% - - Castro JE, et al. Leukemia. 2009; 23:1779-1789. CFAR 14 78% 57% 18 N/A Parikh S, et al. Blood. 2009; 114. Abstract 208. Alemtuzumab 11 64% 27% 11 N/A Hillmen P, et al. J Clin Oncol. 2007;25:5616-5623 Bendamustine 0 - - - - No published studies of bendamustine monotherapy in del(17p) *Patients with mutated TP53 , deleted in del(17p) patients. ***17p deletion and 11q deletion combined; data for 17p deletion were not reported seperately. FR **Addition of rituximab did not result in significant improvement in PFS (PFS for FC and FCR were 12.1 months and 15.4 months, respectively, P = 0.19). We appreciate the efforts of the NCCN NHL Panel in advancing patient care and your specific consideration of alemtuzumab in this regard. FDA status Campath is indicated as a single agent for the treatment of B-CLL. Literature support Alemtuzumab in relapsed/refractory CLL with del(17p) > 20% cells 1. Stilgenbauer S, et al. J Clin Oncol. 2009;27:3994-4001. 2. Fiegl M, et al. Blood. 2008;112. Abstract 3164. 3. Lozanski G, et al. Blood. 2004;103:3278-3281. 4. Cortelezzi A, et al. Leukemia. 2009;Epub.
- 3. 5. Osuji NC, et al. Haematologica. 2005;90:1435-1436. Alemtuzumab in first-line CLL with del(17p) > 20% cells 6. Hillmen P, et al. J Clin Oncol. 2007;25:5616-5623 Additional References Relapsed/Refractory therapies currently listed NCCN Guidelines for R/R CLL with del(17p) > 20% cells 7. Tsimberidou AM, et al. J Clin Oncol. 2008;26(2):196-203. 8. Wierda WG, et al. J Clin Oncol 2009. 2010;28(10):1749-1755. 9. Coiffier B, et al. Blood. 2008;111:1094-1100. 10. Badoux X, et al. Blood. 2009;14. Abstract 1248 and poster board I-270. 11. Thornton PD, et al. Ann Hematol. 2003; 82:759-765. First-line therapies currently listed NCCN Guidelines for CLL with del(17p) > 20% cells 12. Zenz T, et al. Blood. 2009;114. Abstract 1267 13. Tam C, et al. J Clin Oncol. 2008; 26. Abstract 7035. 14. Byrd J, et al. J Clin Oncol. 2006; 24:437-443. 15. Castro JE, et al. Leukemia. 2009; 23:1779-1789. 16. Parikh S, et al. Blood. 2009; 114. Abstract 208.