Autologous Stem Cell Transplantation as Initial Treatment of Diffuse Large B-Cell Lymphoma

1. Autologous Stem Cell Transplantation as Initial Treatment of Diffuse Large B-Cell Lymphoma Amanda F. Cashen, M.D. Grand Rounds 1/6/06

2. Case Presentation 57 yo man with h/o CAD (MI 1995) developed N/V, low grade fever, and fatigue in 12/03. 1/04, he developed confusion and underwent a head MRI? 2.5x2.2 cm mass in the hypothalamus. Patient was started on steroids and his confusion and N/V resolved. 2/04, follow-up MRI ? decrease in the mass to 6 mm. LP with suspicious (but non-diagnostic) cytology. Later in 2/04, pt. developed rapid enlargement of both testicles. U/S? 4.5 cm right testicular mass and at least 4 left testicular masses (largest 1.5 cm) 4/04, abdominal CT? 2 masses in the left kidney and small RP lymph nodes. Biopsy of kidney mass…

3. Case Presentation Diffuse large B-cell lymphoma LDH 611 4/04-8/04, treated with R-CHOP + methotrexate (IV and IT) x 6 cycles Restaging: CSF cytology negative Brain MRI after 3 cycles? decrease in the hypothalamic lesion C/A/P CT after 3 cycles? resolution of kidney masses and LAD Scrotal U/S after 6 cycles? resolution of testicular masses

4. Testicular DLCL Series of 381 patients from 23 institutions treated from 1968-1998 JCO 2003, 21:20-27

5. Case Presentation 11/04, patient underwent BEC + autologous PBSCT in first CR due to high risk of relapse 1/05, XRT to scrotum 11/30/05, no evidence of recurrent lymphoma; persistent pan-hypopituitarism (adrenal insufficiency, hypothyroidism, DI, hypogonadism)

6. Current Standard for DLBCL CHOP is equivalent to, but less toxic than, “third generation regimens” (PROMACE-CytaBOM, M-BACOD, MACOP-B) NEJM 1993, 328:1002 CR 44%; 3-yr OS 54% R-CHOP is superior to CHOP NEJM 2002, 346:235 CR 75% v. 63% 5-yr EFS 47% v. 29% 5-yr OS 58% v. 45% Autologous SCT is the treatment of choice for relapsed disease

7. Prognosis by IPI

8. R-IPI

9. Phase II Studies of Auto for High-Risk Aggressive NHL

10. LNH-87: Survival Benefit of High-Dose Therapy in Poor-Risk Aggressive NHL GELA. JCO 2000,16:3025 542 pts, <55 years old, = 1 adverse risk factor, CR to full-course standard induction therapy (ACVB) Randomized to high-dose therapy + auto or additional conventional dose chemo

11. LNH-87: Survival Benefit of High-Dose Therapy in Poor-Risk Aggressive NHL GELA. JCO 2000,16:3025 Low and low-int. risk pts. had same outcome with either approach 236 high-int. and high risk pts. had improved DFS and OS with transplant (8-yr DFS 55% v 39%, 8-yr OS 64% v. 49%) No toxic deaths in either arm and no MDS in transplant arm

12. Italian Non-Hodgkin’s Study Group: VACOP-B v. VACOP-B plus autologous BMT for advanced diffuse non-Hodgkin’s lymphoma JCO 1998, 16:2796 124 pts < 60 years old with bulky Stage II or Stage III-IV Randomized to standard induction or standard induction + auto (regardless of response to induction) 6-yr OS 65% in both arms Pts with high-int or high risk IPI had improved DFS with transplant (3-yr DFS 87% v. 48%)

13. LNH-93: Shortened First-Line High-Dose Chemotherapy for Patients With Poor-Prognosis Aggressive Lymphoma GELA JCO 2002, 20: 2472 370 pts with high int. and high risk disease randomized to standard induction chemo (ACVBP) or 3 cycles of abbreviated induction chemo followed by auto CR rates were 64% and 63% 5-year OS and EFS for ACVBP and HDT were 60% and 46% v. 52% and 39%.

14. Randomized Study to Evaluate the Use of High-Dose Therapy as Part of Primary Treatment for "Aggressive" Lymphoma GHGLSG. JCO 2002, 20:4413 312 pts < 60 years old with elevated LDH who had at least a minor response to CHOEP x 2 Randomized to another 3 cycles of CHOEP + IFXRT (A) or another 1 cycle of CHOEP then BEAM/auto and IFXRT (B) CR 62.9% in arm A and 69.9% in arm B OS 63% after 3 years in both arms EFS 49% for arm A versus 59% for arm B (P = .22) 6 patients developed secondary neoplasia, 3 in each arm

15. HOVON Studies 27 and 40 JCO 2005, 16:3793 Two Phase II studies in 147 pts. with poor-risk (Stage III/IV + high LDH) aggressive NHL (80% DLBCL) Three cycles of intensified CHOP added to regimen in response to results from previous studies and disappointing results in HOVON-27 No significant differences between the treatment groups

17. Initial Treatment of Aggressive Lymphoma with High-Dose Chemotherapy and Autologous Stem-Cell Support GOELAMS. NEJM 2004, 350:1287 197 patients, age 15-60, with previously untreated aggressive lymphoma (75% DLBCL) Stage III-IV or bulky stage II IPI score of 1-2 (high-risk patients excluded) CHOP q21d x 8 cycles, OR CEEP (cytoxan high dose, epirubicin, vindesine, prednisone) q15d x 2 cycles? stem cell collection post cycle 1 and/or 2? if PR or CR, methotrexate and cytarabine x 1? BEAM + auto

18. Initial Treatment of Aggressive Lymphoma with High-Dose Chemotherapy and Autologous Stem-Cell Support CR rate 57% CHOP group 76% high-dose group (p=0.37) Event-free survival at median f/u 4 yrs. 37% CHOP group 55% high-dose group (p=0.04) OS OS 56 v. 71% (p=0.8) Significantly improved with high-dose therapy in high-int. risk IPI score (44 v. 74%)

19. Conclusions Use of high dose chemotherapy and autologous SCT as part of initial therapy may benefit patients with high-int. or high risk DLBCL. A full course of induction chemotherapy prior to transplant is better than an abbreviated course. Addition of rituximab to induction therapy may eliminate the benefit of upfront auto SCT

20. Outcome in high-intermediate or high risk patients treated with auto SCT

21. Current CALGB Study Patients <65 years old with stage (bulky II)/III/IV aggressive B-cell NHL and high-int. or high risk IPI Treated with R-CHOP x 5 then restaged If PR or CR, randomized to R-CHOP x 3 or auto