MabThera and Autologous Stem Cell Transplant ASCT

1. MabThera® and Autologous Stem Cell Transplant (ASCT)

2. ASCT: Protocol Patients with persistent or recurring lymphoma have few therapeutic options. Introduction of high-dose chemotherapy regimens coupled with autologous stem cell transplantation (ASCT) provided an alternative with a potential for long-term disease-free survival (DFS). Conventional regimens include a debulking and cell-mobilization procedure, followed by BM or stem-cell harvest.74,99 To clear stem-cell collections of contaminating tumor cells, harvests are purged, ex vivo, by positive or negative immunoselection. Patients are then treated with a conditioning regimen, consisting of high-dose chemotherapy with or without total body irradiation (TBI). Following high-dose therapy (HDT), patients are reinfused with purged stem cells.Patients with persistent or recurring lymphoma have few therapeutic options. Introduction of high-dose chemotherapy regimens coupled with autologous stem cell transplantation (ASCT) provided an alternative with a potential for long-term disease-free survival (DFS). Conventional regimens include a debulking and cell-mobilization procedure, followed by BM or stem-cell harvest.74,99 To clear stem-cell collections of contaminating tumor cells, harvests are purged, ex vivo, by positive or negative immunoselection. Patients are then treated with a conditioning regimen, consisting of high-dose chemotherapy with or without total body irradiation (TBI). Following high-dose therapy (HDT), patients are reinfused with purged stem cells.

3. ASCT for Relapsed NHL Higher response and survival rates than with chemotherapy alone Aggressive NHL – PARMA Study EFS 45% vs 12% Indolent NHL – CUP trial: PFS 63% vs 33% (P=0.004) 40%-70% relapse rate after ASCT Possible explanations Residual lymphoma in patient Reintroduction of malignant cells with transplant after ex vivo purging As compared with conventional chemotherapy regimens, high-dose chemotherapy in combination with ASCT resulted in higher response and survival rates.87 Despite the survival advantages posed by this clinical approach, 40% to 70% of patients relapse.86,90 There are several possible explanations for this relapse rate.30,74 Despite receiving HDT, residual lymphoma cells may persist in patients. Lymphoma cells may “survive” the ex vivo purging methods only to be reintroduced into the patient upon transplantation. Lower relapse rates seen after allogeneic BMT support this possibility.As compared with conventional chemotherapy regimens, high-dose chemotherapy in combination with ASCT resulted in higher response and survival rates.87 Despite the survival advantages posed by this clinical approach, 40% to 70% of patients relapse.86,90 There are several possible explanations for this relapse rate.30,74 Despite receiving HDT, residual lymphoma cells may persist in patients. Lymphoma cells may “survive” the ex vivo purging methods only to be reintroduced into the patient upon transplantation. Lower relapse rates seen after allogeneic BMT support this possibility.

4. MabThera® + HDT/ASCT for Relapsed NHL: Rationale In vivo purging agent Ex vivo purging agent Combination with conditioning therapy Post-transplant adjuvant immunotherapy Several studies suggest that the addition of MabThera® to conventional chemotherapy regimens provides significant clinical advantages for patients with NHL. In addition to this observation, there are several potential advantages to adding MabThera® to HDT/ASCT regimens30,74 MabThera® has been shown to deplete B lymphocytes and therefore may function as an in vivo purging method prior to stem cell harvest. In vivo purging may enhance the collection of lymphoma-free stem cells. Several studies have demonstrated the clinical efficacy and safety of re-treatment and planned maintenance therapy with MabThera® in patients with NHL. Therefore, MabThera® may also be given following HDT and ASCT as adjuvant immunotherapy to “mop up” residual lymphoma cells.Several studies suggest that the addition of MabThera® to conventional chemotherapy regimens provides significant clinical advantages for patients with NHL. In addition to this observation, there are several potential advantages to adding MabThera® to HDT/ASCT regimens30,74 MabThera® has been shown to deplete B lymphocytes and therefore may function as an in vivo purging method prior to stem cell harvest. In vivo purging may enhance the collection of lymphoma-free stem cells. Several studies have demonstrated the clinical efficacy and safety of re-treatment and planned maintenance therapy with MabThera® in patients with NHL. Therefore, MabThera® may also be given following HDT and ASCT as adjuvant immunotherapy to “mop up” residual lymphoma cells.

5. In Vivo Purging With MabThera® (Buckstein): Protocol Buckstein et al conducted a trial to evaluate the efficacy of administering MabThera® with high-dose chemotherapy followed by ASCT.5 Uniquely, MabThera® was given with granulocyte-colony stimulating factor (G-CSF) during the mobilization phase to function as an in vivo purge and then following transplantation as maintenance therapy. Eligible patients had 2 relapses of follicular B-cell lymphoma, with Ann Arbor stage III–IV, ECOG PS <2, and were 18 to 65 years old. Stem cells were mobilized with G-CSF for 5 days and then collected via large-volume leukapheresis. All patients received a single dose of MabThera® (375 mg/m2) 2 days before stem cell collection. Patients received CBV (vincristine [2.5 g/m2 over 36 h on day –7]; cyclophosphamide [1.8 g/m2 on days –6 to –4] and carmustine [BCNU] [500 mg/m2 on day –3]) as a salvage therapy regimen. Stem cell reinfusion was conducted on day 0. Following engraftment, patients received regimens of MabThera® (375 mg/m2 weekly x 4) during weeks 8 to11 and 24 to 27. Buckstein et al conducted a trial to evaluate the efficacy of administering MabThera® with high-dose chemotherapy followed by ASCT.5 Uniquely, MabThera® was given with granulocyte-colony stimulating factor (G-CSF) during the mobilization phase to function as an in vivo purge and then following transplantation as maintenance therapy. Eligible patients had 2 relapses of follicular B-cell lymphoma, with Ann Arbor stage III–IV, ECOG PS <2, and were 18 to 65 years old. Stem cells were mobilized with G-CSF for 5 days and then collected via large-volume leukapheresis. All patients received a single dose of MabThera® (375 mg/m2) 2 days before stem cell collection. Patients received CBV (vincristine [2.5 g/m2 over 36 h on day –7]; cyclophosphamide [1.8 g/m2 on days –6 to –4] and carmustine [BCNU] [500 mg/m2 on day –3]) as a salvage therapy regimen. Stem cell reinfusion was conducted on day 0. Following engraftment, patients received regimens of MabThera® (375 mg/m2 weekly x 4) during weeks 8 to11 and 24 to 27.

6. In Vivo Purging With MabThera®:Median PB CD34+ Cell Count Sixteen patients were enrolled with a median age of 46 years.5 Stem cell collection and engraftment data are available for 9 patients who have undergone stem cell mobilization and transplantation. As compared with data from a control group of comparable patients who underwent SCT without MabThera® purge, patients who received MabThera® had a higher median PB CD34+ cell count after 5 days (11.7 x 106/L vs 20.2 x 106/L, respectively) and higher median graft yield (3.1 x 106 CD34+ cells/kg vs 3.7 x 106 CD34+ cells/kg, respectively). The time to neutrophil engraftment and platelet independence seen in the MabThera® and control groups was not significantly different. Sixteen patients were enrolled with a median age of 46 years.5 Stem cell collection and engraftment data are available for 9 patients who have undergone stem cell mobilization and transplantation. As compared with data from a control group of comparable patients who underwent SCT without MabThera® purge, patients who received MabThera® had a higher median PB CD34+ cell count after 5 days (11.7 x 106/L vs 20.2 x 106/L, respectively) and higher median graft yield (3.1 x 106 CD34+ cells/kg vs 3.7 x 106 CD34+ cells/kg, respectively). The time to neutrophil engraftment and platelet independence seen in the MabThera® and control groups was not significantly different.

7. In Vivo Purging With MabThera®: Response Among the 16 patients enrolled in this study, 100% have achieved a clinical response, with CR and unconfirmed CR (CRu) rates of 38% and 63%, respectively.5 Among the 7 patients who presented with the bcl-2 rearrangement, 100% of these patients had molecular responses by 6 months post-transplantation. Among the 16 patients enrolled in this study, 100% have achieved a clinical response, with CR and unconfirmed CR (CRu) rates of 38% and 63%, respectively.5 Among the 7 patients who presented with the bcl-2 rearrangement, 100% of these patients had molecular responses by 6 months post-transplantation.

8. In Vivo Purging With MabThera®: Toxicity All patients completed treatment.7 Pulmonary complications were seen in 63% of patients. Two distinct types of lung toxicity were observed, including an early chemical pneumonitis (n=6) thought to be related to BCNU, and a delayed presentation with idiopathic pulmonary nodules (n=3) or chronic pulmonary infections (n=1). Thirty-eight percent of patients developed chemical pneumonitis within 59 days after transplantation.8 Thirteen percent of patients developed symptomatic hypoxia. There was no significant difference in the MabThera® and control groups for times to neutrophil engraftment (11 days each) and platelet independence (10 days vs 8 days, respectively). All patients completed treatment.7 Pulmonary complications were seen in 63% of patients. Two distinct types of lung toxicity were observed, including an early chemical pneumonitis (n=6) thought to be related to BCNU, and a delayed presentation with idiopathic pulmonary nodules (n=3) or chronic pulmonary infections (n=1). Thirty-eight percent of patients developed chemical pneumonitis within 59 days after transplantation.8 Thirteen percent of patients developed symptomatic hypoxia. There was no significant difference in the MabThera® and control groups for times to neutrophil engraftment (11 days each) and platelet independence (10 days vs 8 days, respectively).

9. In Vivo Purging With MabThera® (Magni): Protocol The efficacy of MabThera® in vivo purging was evaluated in patients with FL or MCL, BM involvement, and PCR-negative disease.74 Based on prior treatment history, patients were treated with a debulking regimen that consisted of either doxorubicin, prednisone, and vincristine, or cisplatin, high-dose cytarabine, dexamethasone chemotherapy. All patients were then treated with high-dose cyclophosphamide (7 mg/m2), high-dose cytarabine (either 1.5 or 2 g/m2 every 12 hours for 6 consecutive days), high-dose melphalan (180 mg/m2), and high-dose mitoxantrone + melphalan (60 and 180 mg/m2, respectively) during the first, third, sixth, and ninth weeks, respectively. Patients also received 6 overall infusions of MabThera® (375 mg/m2). Infusions 1 and 2 were administered 48 hours after cyclophosphamide and 24 hours before the first leukapheresis, respectively. MabThera® infusions 3 and 4 were given 24 hours after the last dose of cytarabine and 24 hours before the first planned leukapheresis after administration of cytarabine, respectively. MabThera® infusions 5 and 6 were given approximately 28 and 35 days, respectively, after the final stem cell autograft, after administration of mitoxantrone and melphalan. Patients received 3 stem cell reinfusions, after high-dose cytarabine and after 2 subsequent courses of melphalan and mitoxantrone + melphalan. The efficacy of MabThera® in vivo purging was evaluated in patients with FL or MCL, BM involvement, and PCR-negative disease.74 Based on prior treatment history, patients were treated with a debulking regimen that consisted of either doxorubicin, prednisone, and vincristine, or cisplatin, high-dose cytarabine, dexamethasone chemotherapy. All patients were then treated with high-dose cyclophosphamide (7 mg/m2), high-dose cytarabine (either 1.5 or 2 g/m2 every 12 hours for 6 consecutive days), high-dose melphalan (180 mg/m2), and high-dose mitoxantrone + melphalan (60 and 180 mg/m2, respectively) during the first, third, sixth, and ninth weeks, respectively. Patients also received 6 overall infusions of MabThera® (375 mg/m2). Infusions 1 and 2 were administered 48 hours after cyclophosphamide and 24 hours before the first leukapheresis, respectively. MabThera® infusions 3 and 4 were given 24 hours after the last dose of cytarabine and 24 hours before the first planned leukapheresis after administration of cytarabine, respectively. MabThera® infusions 5 and 6 were given approximately 28 and 35 days, respectively, after the final stem cell autograft, after administration of mitoxantrone and melphalan. Patients received 3 stem cell reinfusions, after high-dose cytarabine and after 2 subsequent courses of melphalan and mitoxantrone + melphalan.

10. In Vivo Purging With MabThera®: Patient Characteristics Patients enrolled in this study (MabThera® + high-dose chemotherapy; M + HDT) were compared with a group of patients who were prospectively treated with an identical chemotherapy regimen but without MabThera® (HDT).74 Characteristics between the patient groups were similar. The majority of patients had FL or MCL, most had stage IV disease, and virtually all patients had nodal and BM involvement. PB involvement was seen in approximately 1/3 of patients. All 15 of the patients with FL or MCL had previously received 1 chemotherapy regimen. At the time of entry into the study, these patients had progressive disease requiring treatment that recurred either after an initial PR (12 patients) or a CR that lasted <1 year (3 patients). Patients enrolled in this study (MabThera® + high-dose chemotherapy; M + HDT) were compared with a group of patients who were prospectively treated with an identical chemotherapy regimen but without MabThera® (HDT).74 Characteristics between the patient groups were similar. The majority of patients had FL or MCL, most had stage IV disease, and virtually all patients had nodal and BM involvement. PB involvement was seen in approximately 1/3 of patients. All 15 of the patients with FL or MCL had previously received 1 chemotherapy regimen. At the time of entry into the study, these patients had progressive disease requiring treatment that recurred either after an initial PR (12 patients) or a CR that lasted <1 year (3 patients).

11. In Vivo Purging With MabThera®: PCR-Negative Harvests PCR-negative harvests of stem cells were evaluated after cyclophosphamide and cytarabine treatments.74 Following cytarabine treatment, the percentage of PCR-negative cells collected was significantly higher in patients who received MabThera® than in those who did not (93% vs 40%, respectively; P=0.007). Even after ex vivo purging was conducted for 6 of the patients in the HDT group, the percentage of PCR-negative cell harvests remained higher in the M + HDT. In addition, the yield of lymphoma-free cells was also significantly higher in patients who received MabThera® than in those who did not (26 vs 13 CD34+/PCR-negative cells per kg; P=0.029). Of note, in vivo purging was successful in all 7 patients in the M + HDT group with MCL, a population that has been shown to be resistant to both in vivo and in vitro purging. These data suggest that the addition of MabThera® to a HDT regimen may provide a clinical advantage over traditional regimens. PCR-negative harvests of stem cells were evaluated after cyclophosphamide and cytarabine treatments.74 Following cytarabine treatment, the percentage of PCR-negative cells collected was significantly higher in patients who received MabThera® than in those who did not (93% vs 40%, respectively; P=0.007). Even after ex vivo purging was conducted for 6 of the patients in the HDT group, the percentage of PCR-negative cell harvests remained higher in the M + HDT. In addition, the yield of lymphoma-free cells was also significantly higher in patients who received MabThera® than in those who did not (26 vs 13 CD34+/PCR-negative cells per kg; P=0.029). Of note, in vivo purging was successful in all 7 patients in the M + HDT group with MCL, a population that has been shown to be resistant to both in vivo and in vitro purging. These data suggest that the addition of MabThera® to a HDT regimen may provide a clinical advantage over traditional regimens.

12. In Vivo Purging With MabThera®: Response Clinical and molecular response rates of 100% were seen in patients who received MabThera® vs 70% in those who only received HDT.74 Of note, all 9 evaluable patients with MCL had a CR and all patients in the M + HDT group were relapse-free after a median follow-up of 14 months. PCR analyses of BM, PB, and leukapheresed cells were performed after cyclophosphamide and cytarabine treatments. Of note, PCR status was consistent between samples in the HDT group; however, in the M + HDT group, 4 of 13 leukaphereses done in patients with PCR-positive bone marrow were PCR-negative. Patients who received MabThera® required significantly fewer single-donor platelet transfusions (mean, 5 vs 10, respectively; P=0.05) and fewer transfusions of red blood cells (mean 3.6 vs 9, respectively; P=0.03). The time to hematopoietic recovery was similar in both patient groups. This study demonstrated that in vivo purging with MabThera® resulted in higher yields of lymphoma-free cells for transplantation and was associated with higher clinical and molecular response rates than those seen with traditional HDT regimens. Clinical and molecular response rates of 100% were seen in patients who received MabThera® vs 70% in those who only received HDT.74 Of note, all 9 evaluable patients with MCL had a CR and all patients in the M + HDT group were relapse-free after a median follow-up of 14 months. PCR analyses of BM, PB, and leukapheresed cells were performed after cyclophosphamide and cytarabine treatments. Of note, PCR status was consistent between samples in the HDT group; however, in the M + HDT group, 4 of 13 leukaphereses done in patients with PCR-positive bone marrow were PCR-negative. Patients who received MabThera® required significantly fewer single-donor platelet transfusions (mean, 5 vs 10, respectively; P=0.05) and fewer transfusions of red blood cells (mean 3.6 vs 9, respectively; P=0.03). The time to hematopoietic recovery was similar in both patient groups. This study demonstrated that in vivo purging with MabThera® resulted in higher yields of lymphoma-free cells for transplantation and was associated with higher clinical and molecular response rates than those seen with traditional HDT regimens.

13. In Vivo Purging With MabThera® (Flinn): Protocol The potential benefits of administering MabThera® with HDTand ASCT were evaluated.30 Patients received MabThera® (375 mg/m2; IV) over 4 to 8 hours and then 72 hours later received cyclophosphamide (2.5 g/m2; IV) over 1 hour. Mesna (500 mg/m2; IV) was administered 30 minutes before and 3, 6, and 8 hours after cyclophosphamide administration. Patients received G-CSF (10 µg/kg SC) starting the day after chemotherapy and continuing until completion of leukapheresis. Leukapheresis was conducted when the PB CD34 count was ?10/µL. Following leukapheresis, patients received cyclophosphamide(50 mg/kg/d IV for 4 days) and TBI (300 cGy/min using photons from a 4-MV linear accelerator). The entire leukapheresis product was reinfused into patients on day 0 of the transplantation regimen. Post-transplantation, patients received G-CSF on day 1 and continued until the absolute neutrophil count (ANC) was ?1000/ µL for 3 days or until day 30. A second dose of MabThera® was administered after engraftment (ANC of ?1000 for 3 days and an unsupported platelet count of ?20,000 for 7 days). The potential benefits of administering MabThera® with HDTand ASCT were evaluated.30 Patients received MabThera® (375 mg/m2; IV) over 4 to 8 hours and then 72 hours later received cyclophosphamide (2.5 g/m2; IV) over 1 hour. Mesna (500 mg/m2; IV) was administered 30 minutes before and 3, 6, and 8 hours after cyclophosphamide administration. Patients received G-CSF (10 µg/kg SC) starting the day after chemotherapy and continuing until completion of leukapheresis. Leukapheresis was conducted when the PB CD34 count was ?10/µL. Following leukapheresis, patients received cyclophosphamide(50 mg/kg/d IV for 4 days) and TBI (300 cGy/min using photons from a 4-MV linear accelerator). The entire leukapheresis product was reinfused into patients on day 0 of the transplantation regimen. Post-transplantation, patients received G-CSF on day 1 and continued until the absolute neutrophil count (ANC) was ?1000/ µL for 3 days or until day 30. A second dose of MabThera® was administered after engraftment (ANC of ?1000 for 3 days and an unsupported platelet count of ?20,000 for 7 days).

14. In Vivo Purging With MabThera®: Patient Characteristics Twenty-five patients were enrolled in this study. The median age was 51 years.30 The majority of patients (72%) had either FL or MCL. The median number of prior treatments was 1 (range, 1–3). Fourteen patients had received Fludara® or Fludara® + cyclophosphamide, and 14 had received CHOP. Most patients were in their first remission. Twenty-five patients were enrolled in this study. The median age was 51 years.30 The majority of patients (72%) had either FL or MCL. The median number of prior treatments was 1 (range, 1–3). Fourteen patients had received Fludara® or Fludara® + cyclophosphamide, and 14 had received CHOP. Most patients were in their first remission.

15. In Vivo Purging With MabThera®: Response A goal for leukapheresis was set at 5 x 106 CD34+ cells/kg. Among the 25 patients, 23 achieved at least the required minimum collection with a median of 1.07 x 107 CD34+ cells/kg.30 Among the 23 patients who received HDT, 11 were in complete remission at the time of transplantation. Of the remaining 12 patients, 11 were evaluated at 60 days post-transplantation. Six of these patients (55%) achieved a CR, 3 achieved a PR (17%), and 2 had stable disease. PCR analysis indicated that 7 patients presented with either the t(11;14) or t(14:18) translocations. Following in vivo purging with MabThera®, these translocations were undetectable in 6 of 7 (86%) stem cell grafts. Neutrophil recovery and platelet engraftment were rapid. After a median of 99.5 days post-transplantation, 6 patients developed transient neutropenia (ANC <500/mL). MabThera® toxicities were generally infusion-related and mild.A goal for leukapheresis was set at 5 x 106 CD34+ cells/kg. Among the 25 patients, 23 achieved at least the required minimum collection with a median of 1.07 x 107 CD34+ cells/kg.30 Among the 23 patients who received HDT, 11 were in complete remission at the time of transplantation. Of the remaining 12 patients, 11 were evaluated at 60 days post-transplantation. Six of these patients (55%) achieved a CR, 3 achieved a PR (17%), and 2 had stable disease. PCR analysis indicated that 7 patients presented with either the t(11;14) or t(14:18) translocations. Following in vivo purging with MabThera®, these translocations were undetectable in 6 of 7 (86%) stem cell grafts. Neutrophil recovery and platelet engraftment were rapid. After a median of 99.5 days post-transplantation, 6 patients developed transient neutropenia (ANC <500/mL). MabThera® toxicities were generally infusion-related and mild.

16. In Vivo Purging With MabThera® in MCL(Gianni): Protocol Patients were treated with high-dose cyclophosphamide (7 mg/m2), high-dose cytarabine (24 g/m2), high-dose melphalan (180 mg/m2), and high-dose mitoxantrone + melphalan (60 and 180 mg/m2, respectively) during the first, third, sixth, and ninth weeks, respectively. Patients also received 6 infusions of MabThera® (375 mg/m2). Infusions 1 and 2 were administered after cyclophosphamide and before the first leukapheresis, respectively. MabThera® infusions 3 and 4 were given after the last dose of cytarabine and before the first planned leukapheresis after administration of cytarabine, respectively. MabThera ® infusions 5 and 6 were given approximately 28 and 35 days, respectively, after the final stem cell autograft, after administration of mitoxantrone and melphalan. Patients received 3 stem cell reinfusions, after high-dose cytarabine and after 2 subsequent courses of melphalan and mitoxantrone + melphalan. Patients were treated with high-dose cyclophosphamide (7 mg/m2), high-dose cytarabine (24 g/m2), high-dose melphalan (180 mg/m2), and high-dose mitoxantrone + melphalan (60 and 180 mg/m2, respectively) during the first, third, sixth, and ninth weeks, respectively. Patients also received 6 infusions of MabThera® (375 mg/m2). Infusions 1 and 2 were administered after cyclophosphamide and before the first leukapheresis, respectively. MabThera® infusions 3 and 4 were given after the last dose of cytarabine and before the first planned leukapheresis after administration of cytarabine, respectively. MabThera ® infusions 5 and 6 were given approximately 28 and 35 days, respectively, after the final stem cell autograft, after administration of mitoxantrone and melphalan. Patients received 3 stem cell reinfusions, after high-dose cytarabine and after 2 subsequent courses of melphalan and mitoxantrone + melphalan.

17. In Vivo Purging With MabThera® in MCL: Patient Characteristics Twenty-eight patients were enrolled with a median age of 49. The majority of patients had Ann Arbor stage IV disease and an IPI score of 1–2. Approximately half of the patients were positive for the bcl-1 rearrangement, and approximately 1/3 of the patients hadB symptoms, a mass >10 cm, or abnormal LDH levels. Twenty-eight patients were enrolled with a median age of 49. The majority of patients had Ann Arbor stage IV disease and an IPI score of 1–2. Approximately half of the patients were positive for the bcl-1 rearrangement, and approximately 1/3 of the patients hadB symptoms, a mass >10 cm, or abnormal LDH levels.

18. In Vivo Purging With MabThera® in MCL: Response Among the evaluable patients, 97% had clinical CRs and 100% had molecular CRs. Only 3 patients experienced adverse events (progression, undefined toxicity, and relapse). Among the evaluable patients, 97% had clinical CRs and 100% had molecular CRs. Only 3 patients experienced adverse events (progression, undefined toxicity, and relapse).

19. In Vivo Purging With MabThera® in MCL: 3-Year Survival The 3-year EFS rate (median, 21 months follow-up) was 85% in patients treated with sequential MabThera® + high-dose therapy (sHDT), 19% in historical controls treated with anthracycline-containing regimens. The 3-year EFS rate (median, 21 months follow-up) was 85% in patients treated with sequential MabThera® + high-dose therapy (sHDT), 19% in historical controls treated with anthracycline-containing regimens.

20. MabThera® EBMTLYM1 Trial: Protocol A randomized phase III study is being conducted to evaluate the efficacy of MabThera® purging and maintenance therapy with PBSCT in patients with relapsed follicular NHL. Patients are stratified according to the remission type (eg, complete vs good partial) and the number (eg, second vs third) with which they present. Patients receive induction chemotherapy with cyclophosphamide over 3 to 4 hours. G-CSF is given daily beginning 24 hours following cyclophosphamide therapy. Patients are then staged and randomized into 4 treatment arms. Patients in treatment arms I and II receive MabThera® in vivo purging and those in arms III and IV do not. PBSCs are collected 8 to 12 days following cyclophosphamide. Within 4 weeks of PBSC collection, patients receive BCNU over 2 hours on day –6, etoposide over 2 hours on days –5 to –2, cytarabine over 5 minutes twice daily on days –5 to –2, and melphalan over 10 to 15 minutes on day –1. PBSCs are reinfused on day 0. Patients are further randomized to receive either MabThera® maintenance therapy (arms I and III) or observation only (arms II and IV). A randomized phase III study is being conducted to evaluate the efficacy of MabThera® purging and maintenance therapy with PBSCT in patients with relapsed follicular NHL. Patients are stratified according to the remission type (eg, complete vs good partial) and the number (eg, second vs third) with which they present. Patients receive induction chemotherapy with cyclophosphamide over 3 to 4 hours. G-CSF is given daily beginning 24 hours following cyclophosphamide therapy. Patients are then staged and randomized into 4 treatment arms. Patients in treatment arms I and II receive MabThera® in vivo purging and those in arms III and IV do not. PBSCs are collected 8 to 12 days following cyclophosphamide. Within 4 weeks of PBSC collection, patients receive BCNU over 2 hours on day –6, etoposide over 2 hours on days –5 to –2, cytarabine over 5 minutes twice daily on days –5 to –2, and melphalan over 10 to 15 minutes on day –1. PBSCs are reinfused on day 0. Patients are further randomized to receive either MabThera® maintenance therapy (arms I and III) or observation only (arms II and IV).

21. MabThera® EBMTLYM1 Trial: Eligibility Criteria Eligible patients have relapsed, follicular, CD20+ NHL, a WHO PS score of 0-1, a platelet count >100 x 109/L after induction therapy, and are at least 18 years old. Patients are not eligible if they have received prior therapy with radiation to >30% of one’s BM, more than 3 chemotherapy regimens for NHL, or transplantation. Patients are also excluded if they have impaired renal, hepatic, cardiac and pulmonary function, histologic transformation to high grade, or exhibit CNS involvement, HIV+, hepatitis B+, or hepatitis C+. Eligible patients have relapsed, follicular, CD20+ NHL, a WHO PS score of 0-1, a platelet count >100 x 109/L after induction therapy, and are at least 18 years old. Patients are not eligible if they have received prior therapy with radiation to >30% of one’s BM, more than 3 chemotherapy regimens for NHL, or transplantation. Patients are also excluded if they have impaired renal, hepatic, cardiac and pulmonary function, histologic transformation to high grade, or exhibit CNS involvement, HIV+, hepatitis B+, or hepatitis C+.

22. MabThera® + ASCT: Summary CR and molecular response rates up to 100% Higher yield of PCR-negative stem cells with MabThera® + HDT vs HDT alone  Toxicity related to MabThera® mild and transient The combination of MabThera® with ASCT resulted in CR and molecular response rates up to 100%. As compared with patients who received conventional HDT regimens with ASCT, patients who also received MabThera® had higher yields of PCR-negative stem-cell harvests. The addition of MabThera® to HDT + ASCT regimens did not appear to increase toxicity. The combination of MabThera® with ASCT resulted in CR and molecular response rates up to 100%. As compared with patients who received conventional HDT regimens with ASCT, patients who also received MabThera® had higher yields of PCR-negative stem-cell harvests. The addition of MabThera® to HDT + ASCT regimens did not appear to increase toxicity.