Age-Stratified Treatment-Modalities for Patients with Primary CNS Lymphoma: Results of a Phase II Study and Two Pilot-Studies.

Abstract Background: Primary NHL of the CNS (PCNSL) are associated with a dismal prognosis despite initial response to steroids and radiotherapy (RT). Addition of high-dose methotrexate (HD-MTX) to RT has improved the prognosis of patients (pts) with PCNSL. However, the majority of pts eventually relapse. To improve survival we performed a multicenter phase II study with early high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) followed by hyperfractionated whole-brain radiation (WBRT) for 30 pts under 65yrs. Five-year overall survival rates of 69% for all pts and 87% for 23 pts receiving HDT and ASCT could be reported (Illerhaus et al., J Clin Oncol. 2006). Purpose: Here we present the results of 1) a pilot study for HDT and ASCT with WBRT restricted to residual disease in pts ≤65 years; 2) a multicenter phase II study for MTX-based CT and 3) a pilot-study for chemo-immunotherapy in pts > 65 years. Methods and Results: New treatment regimen for pts ≤65 years: CT consists of 4 cycles HD-MTX (8g/m2), 2 cycles AraC (2×3g/m2) and thiotepa (40mg/m2) followed by HDT with BCNU (400mg/m2) and thiotepa (4×5mg/kg) before ASCT. To date, 12 pts have been treated in this single center pilot-study. After HDT and ASCT 7/10 pts (70%) responded with complete remission (CR), 2/10 pts with partial remission (PR), 1 pt showed progressive disease (PD) and died after refusing RT. The 2 pts with PR have been irradiated resulting in continuous CR. Two pts were off study due to refractory disease. After a median follow-up of 17 months (mo) (range 4–41) 9/12 pts are alive in continuous CR. One pt developed a systemic relapse and died 8 months after ASCT. Overall, the treatment was well tolerated without grade IV toxicity. Patients >65 yrs, MCP-protocol: Thirty-two pts (17 female, 15 male, median age 71 yrs, range 57–79y) were treated in a phase II trial with 3 repetitive cycles of HD-MTX (3g/m2, d1, 15, 30) combined with procarbazine (60 mg/m2 p.o., d1-10) and CCNU (110 mg/m2 p.o., d 1). There was no lower limit of Karnofsky Performance Status. Thirty-two pts received 1 cycle, 17 pts received 2 cycles and 10 pts received 3 cycles. Best documented response in 25 evaluable pts were CR in 13/32 (41%), PR in 7/32 (22%) and PD 5/32 (16%) pts. Five of 32 pts developed severe renal impairment after MTX and were treated off-study. One patient died due to neutropenic fever. With a median follow-up of 64 mo (range 0–82 mo), the 5-year overall survival probability currently is 30.5%, the median survival is 15 mo. As of July 2006 9/32 (28%) pts are alive, 8 without evidence for leukoencephalopathy. New treatment regimen for pts >65 years, R-MCP-Protocol: In a subsequent pilot-phase rituximab has been added before each MTX-application. In a single center pilot-phase, 9 pts were treated within the protocol. The response rates were CR in 4/7 (57%) evaluable pts, PR, SD and PD, each in one pt, respectively. One patient received only one dose of MTX due to liver toxicity and developed CR with rituximab as single agent. To date, after a median follow-up of 4 mo (range 0–11mo) 8 of 9 pts are alive. Conclusion: The protocols presented here are safe and show high efficacy in treating patients with PCNSL in both age-groups. The addition of rituximab to MTX-based chemotherapy is promising and warrants further investigation.

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Primary CNS Lymphoma - High-Dose-Chemotherapy with Autologous PBSCT and Hyperfractionated Radiotherapy as First-Line-Therapy - Results of a Multicenter Phase II Study.

Blood ◽

10.1182/blood.v106.11.680.680 ◽

2005 ◽

Vol 106 (11) ◽

pp. 680-680 ◽

Cited By ~ 1

Author(s):

Gerald Illerhaus ◽

Reinhard Marks ◽

Guenther Derigs ◽

Christan Peschel ◽

Norbert Frickhofen ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Study ◽

High Dose Chemotherapy ◽

Water Soluble ◽

High Dose ◽

Who Grade ◽

Hyperfractionated Radiotherapy ◽

Multicenter Phase ◽

Autologous Pbsct

Abstract Primary NHL of the CNS (PCNSL) carries a poor prognosis despite initial response to steroids and radiotherapy (RT). Addition of methotrexate (MTX) to RT has improved the prognosis of patients (pts) with PCNSL, but a significant proportion of patients are still not cured. To improve relapse free survival and to reduce neurotoxicity we initiated a multicenter phase II study with early dose intensified chemotherapy (CT) and PBSCT followed by hyperfractionated whole-brain radiation (WBRT) for pts aged under 65yrs. The use of high-dose (HD) lipophilic blood-brain-barrier-penetrating agents (BCNU, Thiotepa) in addition to maximum doses of water-soluble agents (MTX, AraC) is a novel approach in the treatment of PCNSL. To reduce the risk of delayed neurotoxicity, intrathecal chemotherapy was completely avoided and CT was administered before RT. Induction treatment included 3 repetitive cycles of HD-MTX (8g/m2). AraC (2x 3g/m2) and thiotepa (40mg/m2) followed by rG-CSF were used for stem-cell-mobilisation. The conditioning regimen included BCNU (400mg/m2) and thiotepa (2x5mg/kgBW) prior PBSCT. Additional hyperfractionated WBRT (45 Gy, 2x1Gy/d) was administered as consolidation. From 1999 to 2003 thirty pts (age under 65y) have been enrolled in the study (median age 54, range 30–64y). 21 of 30 pts responded to HD-MTX (6 CR, 15 PR). 22/30 pts received high dose CT and autologous PBSCT according to the protocol. Four pts refractory to MTX proceeded to RT directly and 1 patient died from PD subsequently. One patient died because of treatment-related liver toxicity after High-Dose MTX. Beside cytopenia no severe acute toxicities [WHO Grade 3 or 4] were observed after high-dose chemotherapy. After intention-to-treat analysis the response-rate was 89%. All patients that completed the protocol obtained CR (22/22). Three of these pts died, two died during follow-up due to relapse after 1 or 5 years respectively, the third patient died after 25 mo due to progressive heart failure. With a median follow-up of 42 months (range 3–84 mo) the overall survival of all pts included and pts that fulfilled the protocol is 71,3% and 86,5%, respectively. We conclude that sequential systemic application of high-dose differential acting cytostatic agents with consolidating hyperfractionated radiotherapy is very effective and well tolerable. In a new multicenter phase II study, pts will be treated with more intensive high dose CT and PBSCT omitting consolidating radiotherapy.

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1142: Multicenter Phase II Study of Combined Neoadjuvant Docetaxel and Hormone Therapy Prior to Radical Prostatectomy for Patients with High Risk Localized Prostate Cancer: Pathologic Outcomes and 3-Year Follow-Up Analyses

The Journal of Urology ◽

10.1016/s0022-5347(18)31356-9 ◽

2007 ◽

Vol 177 (4S) ◽

pp. 377-377

Author(s):

Martin E. Gleave ◽

Kim Chi ◽

Joseph L. Chin ◽

Eric Winquist ◽

Laurence H. Klotz ◽

...

Keyword(s):

Prostate Cancer ◽

High Risk ◽

Radical Prostatectomy ◽

Hormone Therapy ◽

Phase Ii ◽

Phase Ii Study ◽

Localized Prostate Cancer ◽

Multicenter Phase

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Long-Term Follow-Up of a Pilot Phase II Study with Neoadjuvant Epidoxorubicin, Etoposide and Cisplatin in Gastric Cancer

Oncology ◽

10.1159/000080285 ◽

2004 ◽

Vol 67 (1) ◽

pp. 48-53 ◽

Cited By ~ 19

Author(s):

C. Barone ◽

A. Cassano ◽

C. Pozzo ◽

D. D’Ugo ◽

G. Schinzari ◽

...

Keyword(s):

Gastric Cancer ◽

Phase Ii ◽

Phase Ii Study ◽

Pilot Phase ◽

Long Term Follow Up

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Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin’s Lymphoma (NHL): Follow-Up Results of a Phase II Study Sphingosomal Vincristine in CHOP +/− Rituximab Is a Promising New Treatment for Patients with High Risk Untreated Aggressive Non-Hodgkin’s Lymphoma (NHL): Follow-Up Results of a Phase II Study.

Blood ◽

10.1182/blood.v104.11.4602.4602 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4602-4602

Author(s):

Maria Alma Rodriguez ◽

Andreas Sarris ◽

Nam H. Dang ◽

Luis Fayad ◽

Andre Goy ◽

...

Keyword(s):

High Risk ◽

Phase Ii ◽

Hodgkin’S Lymphoma ◽

Phase Ii Study ◽

Hodgkin's Lymphoma ◽

Total N ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

New Treatment

Abstract Sphingosomal vincristine (SV) is a novel formulation of vincristine encapsulated in sphingomyelin liposomes or ‘sphingosomes’. SV was well tolerated with 45% ORR in multiply relapsed aggressive NHL (ASH Abst.412, 1999). The addition of rituximab to CHOP improves response in aggressive B-cell lymphomas in the elderly (Coiffier et al., NEJM2002:346; 235–42). Based on these data, a phase II study of RCHOP, substituting SV for free vincristine, was undertaken in patients with previously untreated aggressive NHL (excluding rituximab if T-cell lymphoma). Methods: Patients were treated with standard dose CHOP that included SV 2.0 mg/m2 without dose capping ± rituximab 375 mg/m2, given every 21 days for 6 to 8 courses (ASH Abst.338, 2002). Results: Of 73 patients enrolled in the study, 68 were evaluable for response. Median age was 63 (range 22–80). IPI score was 0–2 in 44 pts and ≥ 3 in 24 pts. Patients received a median of 6 study treatments (range 1–8). ORR was 93% (63/68 pts) with 62 pts achieving CR and Cru (91%), and 1 PR (2%). 3 pts had PD (4%) and 2 were not assessed for response (3%). The median PFS and OS have not been reached at a median follow up of 29.5 months. Responses according to IPI score were as follows: Results IPI 0–2 (n=44) IPI ≥3 (n=24) Total (n=68) ORR 93% (41) 92% (22) 93% (63) −CR 77% (34) 88% (21) 81% (55) −Cru 14% (6) 4% (1) 10 (7) −PR 2% (1) 0% (0) 2% (1) PD 5% (2) 4% (1) 4% (3) Not Assessed 2% (1) 4% (1) 3% (2) The probability of being progression free at 25 months was 86% (5 relapses and 1 death, reason unknown) for pts with IPI 0–2 and 77% (6 relapses) for pts with IPI ≥3. Overall survival probability was 94% at 28 months (1 death in the group with IPI 0–2 and 2 deaths in the group with IPI ≥3). Neuropathy was generally mild (Gr.1–2). Hematological toxicities were as follows: 64% Gr.3–4 neutropenia, 6% Gr.3 anemia, and 14% Gr.3–4 thrombocytopenia. Conclusions: CHOP plus rituximab regimen with sphingosomal vincristine substituted for free vincristine demonstrated promising activity with durable responses similar in both groups of patients with IPI score 0–2 and IPI ≥ 3. The treatment was well tolerated with only mild neurotoxicity.

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Durable Responses with Bendamustine Monotherapy In Patients with Relapsed/Refractory Indolent B-Cell Non-Hodgkin Lymphoma (B-NHL) and Mantle-Cell Lymphoma (MCL): Updated Follow-up Data From a Japanese Multicenter Phase II Study

Blood ◽

10.1182/blood.v116.21.4884.4884 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4884-4884 ◽

Cited By ~ 1

Author(s):

Kuniaki Itoh ◽

Kiyoshi Ando ◽

Michinori Ogura ◽

Kenichi Ishizawa ◽

Takashi Watanabe ◽

...

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Phase Ii ◽

Group Performance ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Multicenter Phase ◽

Short Period ◽

Mantle Cell

Abstract Abstract 4884 Background: Bendamustine is an alkylating agent with a unique mechanism of action and has demonstrated efficacy as a single agent for the treatment of relapsed or refractory indolent B-NHL or MCL. We conducted a multicenter, phase II study of bendamustine in Japanese patients with indolent B-cell NHL or MCL, reporting an overall response rate of 91% (90% in indolent B-NHL and 100% in MCL) according to International Workshop Response Criteria after a median follow-up of 12.6 months (Ohmachi et al. Cancer Sci 2010 [Epub ahead of print]). Here we report the updated progression-free survival (PFS) data, including median PFS, which had not been reached at the time of previous reports. Patients and Methods: Eligible patients (aged 20–75 years; Eastern Cooperative Oncology Group performance status of 0 or 1) with measurable, pathologically confirmed indolent B-NHL or MCL that failed to respond to, or relapsed after, prior therapy were enrolled. Bendamustine 120 mg/m2 was administered intravenously over 60 minutes on days 1 and 2 every 21 days for up to 6 cycles. PFS was assessed 3 months after completion of the last cycle, and then at 3-month intervals. Results: A total of 69 patients, aged 33–75 years, were enrolled: 58 with indolent B-NHL, mainly follicular lymphoma (n = 52), and 11 with MCL. Patients had primarily stage III or IV disease. The median number of prior regimens was 2 (range, 1–9) for patients with indolent B-NHL and 4 (range, 1–16) for those with MCL. A median of 5 (range, 1–6) bendamustine cycles were administered, with 72% of patients completing 3 or more cycles. The median follow-up time for all patients is 20.6 months (range, 2.5–27.2 months). The median PFS was 21.1 months (95% CI, 15.8-NA; NA = not available due to short period of observation): 20.0 months (95% CI, 12.3-NA) in indolent B-NHL, and 21.7 months (95% CI, 16.5-NA) in MCL. Estimated 2-year PFS rates were 45.2% and 34.1% in indolent B-NHL and MCL, respectively. Conclusions: Bendamustine monotherapy is highly effective in patients with relapsed or refractory indolent B-NHL and MCL. The durable responses observed in this study strongly support the use of bendamustine in these patients and are particularly encouraging in the relapsed or refractory MCL population. Disclosures: Off Label Use: Bendamustine is a novel alkylator that has shown efficacy and safety in patients with indolent lymphomas, and particularly encouraging is the activity in patients with mantle cell lymphoma, which is difficult to treat. Although bendamustine is currently investigational in Japan, approval for relapsed/refractory indolent NHL and mantle cell lymphoma is anticipated in October 2010.

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