Frequency of NHL Subtypes in Adults

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1 Chemotherapy Options Stephanie A. Gregory, M.D. The Elodia Kehm Professor of Medicine Director, Section of Hematology Rush University Medical Center Chicago, Illinois

2 Frequency of NHL Subtypes in Adults Composite lymphomas (12%) Follicular (22%) Small lymphocytic (6%) Mantle cell (6%) Peripheral T-cell (6%) Marginal zone B-cell, MALT (5%) Diffuse large B-cell (31%) Other subtypes with a frequency <2% (9%) Marginal zone B-cell, nodal (1%) Lymphoplasmacytic (1%) Armitage, et al., J Clin Oncol. 1998;16:

3 Follicular Lymphoma Clinical Transformation is common Spontaneous regression occurs in up to 30% of cases Pathology Subtypes: Grade 1, 2, 3 CD20+, CD10+, CD5-, CD3- Molecular t(14;18) translocation BCL2 is over expressed

4 Clinical Characteristics of Patients with Follicular Lymphoma Characteristic Median Age Result 59 years Stage I 18% II 11% III 16% IV 51%

5 Follicular Lymphoma Histological Transformation Clinical recognized in 40-60% of patients At autopsy in >90% Heralded by a change in the clinical course: New symptoms Rapidly progressive (often localized) Elevated LDH Gallium avidity Generally poor prognosis Extended survival possible when large cell component can be cured (localized, minimal prior therapy)

6 Follicular Lymphoma: Common Management Approach After Staging Evaluation Localized Advanced Low Tumor Burden Advanced High Tumor Burden Involved/Extended Field Radiation Observation Therapy Therapy

7 Follicular Lymphoma Observation as Initial Therapy Prospective and retrospective analyses have demonstrated: 3 year median time to chemotherapy No survival disadvantage Same rate of histological transformation

8 Chemotherapy as Initial Therapy in Advanced Stage Follicular Lymphoma High response rate; CR in 40-70% Median CR duration ~3 years, but 25% of CRs last 10 years Chemosensitivity is frequently retained at relapse often to the same agents

9 Indolent NHL Responds to Repeated Chemotherapy with Shorter Durations of Response Responding patients (n = 110) in remission through 4 treatments with the same chemotherapy regimen Patients in remission (%) st 2nd Chemotherapy treatment (no.) Duration (months) th 3rd Years Gallagher, et al., J Clin Oncol. 1986;4:

10 Traditional Treatment Approaches for Advanced Stage Follicular Lymphoma Oral chlorambucil/cyclophosphamide +/- prednisone CVP CHOP Fludarabine-based therapy

11 Initial Therapy with Alkylator-Based Regimens Regimen Chlorambucil (St. Barts) CVP (Europe) CHOP-B (CALGB) ProMACE/MOPP (NCI) Response (%) OR CR Year (%) OS DFS >50 N/A 60 N/A

12 Low-grade NHL: Overall Survival with Doxorubicin-based Therapy J Clin Oncol 11:614, 1993

13 Initial Therapy with Fludarabine-Based Regimens 5-Year Regimen % Response (CR) Survival Fludarabine 68 (38) 68% (GELF) FN 94 (44) 88% (4-year) (SWOG) FND 98 (71) 84% (MDACC)

14 Fludarabine and Mitoxantrone in Untreated Stages III & IV Low-Grade Lymphoma (S9501) 78 eligible patients: 66 (85%) follicular 12 (15%) SLL 94% overall response 44% CR Median follow-up of 5.5 years: median PFS = 32 months 4-year PFS = 38% 4-year overall survival (OS) = 88% ß 2 microglobulin and LDH - predictor of outcome. Overall survival less in patients with high LDH and elevated ß 2 microglobulin. Velasquez, et al., J Clin Oncol 21(10), 2003

15 Fludarabine and Mitoxantrone (FN) in Low- Grade Lymphoma (S9501) 100% Progression-Free Survival Compared With Other SWOG Studies 80% At Risk Failures 4-Year Estimate 60% CHOP (1974) CHOP (1977) FN (1995) ProMACE-MOPP (1988) % 41% 38% 46% 40% 20% 0% Years From Registration Velasquez, et al., J Clin Oncol. 2003;21: Figure reprinted with permission from the American Society of Clinical Oncology.

16 Fludarabine and Mitoxantrone (FN) in Low-Grade Lymphoma (S9501) 100% 80% 60% Overall Survival Compared With Other SWOG Studies CHOP (1974) CHOP (1977) FN (1995) ProMACE-MOPP (1988) At Risk Deaths Year Estimate 73% 62% 88% 77% 40% 20% 0% Years From Registration Velasquez, et al., J Clin Oncol. 2003;21: Figure reprinted with permission from the American Society of Clinical Oncology.

17 Chemotherapy in Patients with Relapsed/Refractory Follicular Lymphomas Drug % Response (CR) Duration Chlorambucil 68 ~10 mo. Fludarabine 53 (6) 7 mo. FND 94 (47) 21 mo. CR 9 mo. PR EPOCH 53 (12) 4 mo. MINE 63 (11) --

18 Fludarabine, Mitoxantrone, and Dexamethasone (FND) in Recurrent Indolent NHL (N=51) Regimen: Fludarabine 25 mg/m 2 /d IV, days 1-3 Mitoxantrone 10 mg/m 2 IV, day 1 Dexamethasone 20 mg/d IV or PO, days 1-5 PCP prophylaxis (eg, TMP-SMX) Overall RR 94% (CR 47%, PR 47%) Median duration of CR - 21 months, PR - 9 months McLaughlin et al. J Clin Oncol. 1996;14:

19 FND for Recurrent Indolent NHL McLaughlin, et al., J Clin Oncol 14: , 1996

20 Take Home Message: Chemotherapy in Low-Grade NHL No difference in overall survival when comparing singleagent therapy vs. combination therapy Addition of an anthracycline to combination chemotherapy does not affect overall survival Molecular responses not studied in single-agent or early combination therapy trials but are reported with the FND regimen