Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma.

PURPOSE: Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. PATIENTS AND METHODS: Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. RESULTS: Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenstrom's macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study. CONCLUSION: Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.     

Phase II study of docetaxel in patients with relapsed or refractory malignant lymphoma

We report the activity and toxicity of docetaxel in 12 evaluable heavily pretreated patients with relapsed and refractory non-Hodgkin's lymphoma and Hodgkin's disease. In all, 42% achieved a partial response, 25% achieved stable disease. Median duration of response was 16 (10-21) weeks. The median overall survival was 70 (9-178) weeks and for responders it was 120 (22-178) weeks. One patient developed one episode of neutropenic sepsis. Docetaxel has limited activity in this group of patients.     

ESHAP方案治疗复发或难治性侵袭性非霍奇金淋巴瘤

 【摘要】　目的　观察ESHAP方案作为解救化疗方案治疗复发或难治性侵袭性非霍奇金淋巴瘤（NHL）的疗效和安全性。方法　选取38例复发或难治性侵袭性NHL患者，使用ESHAP方案（依托泊苷、甲泼尼龙、顺铂、阿糖胞苷）作为解救方案进行化疗。结果　38例患者各接受了2～6个周期ESHAP方案化疗，总的客观有效率为55.3 %，完全缓解率26.3 %；主要不良反应为骨髓抑制伴感染，均可耐受。结论　ESHAP方案是治疗复发或难治性侵袭性NHL安全有效的解救方案之一。     

Phase II study of gemcitabine-dexamethasone with or without cisplatin in relapsed or refractory mantle cell lymphoma.

Single-agent gemcitabine has shown encouraging results in patients with mantle cell lymphoma (MCL). This phase II study further explored the potential of a gemcitabine-based regimen in patients with relapsed or refractory MCL. Patients <70 years old received the PDG regimen: gemcitabine (1000 mg/m(2), days 1 and 8), dexamethasone (40 mg/m(2), days 1-4), and cisplatin (100 mg/m(2), day 1). Patients >/=70 years of age received dexamethasone and gemcitabine only (DG regimen). Thirty patients (12 in the DG group, 18 in the PDG group) with a median age 66.5 years (range, 47-81) received a median of six cycles in both groups. The overall response rate was 36.4% [95% confidence interval (CI), 15.2% to 64.6%] with the DG regimen and 44.4% (95% CI 24.6% to 66.3%) with the PDG regimen. The median progression-free survival was 3 months (95% CI 0.0-7.9) in the DG group and 8.5 months (95% CI 4.8-12.2) in the PDG group. With a median follow-up of 38.8 months, 13 patients (including 11 given PDG) are still alive. DG was well tolerated, and thrombocytopenia was the most prevalent toxicity in patients receiving PDG. Both regimens deserve to be further investigated as a backbone for combination chemotherapy in patients with MCL.     

Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma.

BACKGROUND: Bendamustine, an alkylating agent with a nitrogen mustard group and a purine-like benzimidazol group, has been shown to be effective in several solid tumors and indolent non-Hodgkin's lymphomas, but has not yet been studied for efficacy in aggressive lymphomas. PATIENTS AND METHODS: We conducted a phase II study in patients with relapsed or refractory high-grade non-Hodgkin's lymphomas, using bendamustine at a dose of 120 mg/m(2) on days 1 and 2, every 3 weeks for up to six cycles. Twenty-one patients were enrolled; 18 were evaluable for response and toxicity, 10 of whom were refractory to previous chemotherapy. RESULTS: With three patients achieving a complete response (at 6, >or=8 and >or=22 months) and five a partial response (three at 2 months, one at 3 months and one at 10 months), the total response rate of the evaluable patients was 44% (eight out of 18; 38% of all patients). Two complete and two partial responders were refractory to prior treatment. In 10 patients, treatment had to be stopped after one to three cycles due to progressive disease or hematological toxicity (n = 2). Non-hematological side effects were mild. Eight (13%) WHO grade 3 and no grade 4 events were observed in 60 evaluable treatment cycles. Hematologic toxicity was moderate (grade 3 and 4): anemia in five cycles (8%), leukopenia in seven (12%) and thrombocytopenia in eight (13%). CONCLUSIONS: Bendamustine as a single agent is effective against aggressive lymphoma, even in cases of refractory disease. Further studies are warranted to determine the significance of bendamustine in the treatment of aggressive lymphomas.     

Phase II study of oral fludarabine in combination with rituximab for relapsed indolent B-cell non-Hodgkin lymphoma

Oral fludarabine is more convenient than intravenous fludarabine in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine in combination with rituximab in patients with relapsed indolent B-cell non-Hodgkin lymphoma (B-NHL), we conducted a multicenter phase II study. Patients with relapsed indolent B-NHL with two or fewer prior regimens and up to 16 doses of rituximab were eligible. Patients received 375 mg/m² rituximab on day 1, and 40 mg/m² oral fludarabine once daily on days 1 through 5 every 28 days for up to six cycles. The primary endpoint was the overall response rate. Forty-one patients were enrolled, including 38 (93%) with follicular lymphoma. Thirty-four patients (83%) had received rituximab as prior therapy. Twenty-seven patients (66%) completed the planned six cycles. Dose reduction of oral fludarabine was required in 17 patients (41%). The overall response rate was 76% (31 of 41 patients; 95% confidence interval, 60–88%) with a complete response rate of 68% (28 of 41 patients; 95% confidence interval, 52–82%). Median progression-free survival for the 41 patients was 19.7 months (95% confidence interval, 12.3–26.5 months). Hematological toxicities, including grade 4 neutropenia (68%), were the most frequent toxicities. Non-hematological toxicities were mild, except for one patient who died of Pneumocystis jiroveci pneumonia 4 months after the protocol treatment. In conclusion, oral fludarabine in combination with rituximab is a highly effective and convenient therapy for patients with relapsed indolent B-NHL who have mostly been pretreated with rituximab. (ClinicalTrials.gov number, NCT00311129.) ( Cancer Sci  2009; 100: 1951–1956)     

Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma.

BACKGROUND: To evaluate the efficacy and feasibility of rituximab monotherapy in Japanese patients with relapsed or refractory aggressive B-cell lymphoma. PATIENTS AND METHODS: Sixty-eight patients were treated with rituximab at 375 mg/m(2) by eight consecutive weekly infusions. Pretreatment variables affecting overall response rate (ORR) and progression-free survival (PFS) and the relationship between pharmacokinetic parameters and efficacy were analyzed. RESULTS: The ORRs of 68 enrolled patients and 57 eligible patients were 35% [95% confidence interval (CI) 24% to 48%] and 37% (95% CI 25% to 51%), respectively. Median PFS of 53 evaluable patients was 52 days, whereas time to progression of 21 eligible responders was 245 days. Mild to moderate infusion-related toxicities were observed frequently at the first infusion, but all of them were reversible. Elevated lactate dehydrogenase (LDH) and refractoriness to prior chemotherapy were unfavorable factors affecting ORR and PFS (P <0.01). Serum trough levels of rituximab and area under the concentration-time curve for responders were higher than for non-responders (P <0.05). CONCLUSIONS: Eight consecutive weekly infusions of rituximab have significant anti-lymphoma activity for relapsed or refractory aggressive B-cell lymphoma. Several pretreatment variables and serum rituximab levels are useful for predicting its efficacy.     

DNCE方案治疗复发或难治的侵袭性非霍奇金淋巴瘤

目的 探讨DNCE方案作为二线解救方案治疗复发或难治的侵袭性非霍奇金淋巴瘤(NHL)的有效性和安全性.方法 经病理学或组织学证实的、且一线CHOP方案治疗后进展的侵袭性恶性NHL患者69例,按信封法随机分为DNCE方案组与DICE方案组.其中DICE组37例,采用地塞米松(DXM)20 mg,静脉滴注,d1～d4;异环磷酰胺(IFO)1 S/m2,静脉滴注,d1～d4;Mesna解救400 mg,静脉滴注q8h,d1～d4;顺铂(DDP)25 mg/m2,静脉滴注,d1～d4;依托泊苷(Vp-16)100 ms/m2,静脉滴注,d1～d4.21～28d为1个周期.DNCE组32例,采用DXM、DDP、Vp-16的剂量与DICE方案相同;NVB 25 ms/m2,静脉滴注,d1和d5.21～28d为1个周期.所有患者均完成≥2个周期的化疗.结果 DNCE组中,完全缓解(CR)6例,部分缓解(PR)12例,有效率为56.3%(18/32);DICE组中,CR 4例,PR 13例,有效率为45.9%(17/37).DNCE组的疗效优于DICE组,但两组间差异无统计学意义(P>0.05).DICE组的1、3、5年生存率分别为86.5%、58.3%和42.9%,DNCE组分别为87.5%、63.2%和38.5%,两组间差异无统计学意义(P>0.05).两组主要的不良反应为骨髓抑制和消化道反应,表现为粒细胞、血小板减少及恶心、呕吐等.DNCE组的骨髓毒性轻于DICE组,差异有统计学意义(P<0.05).结论 DNCE方案治疗侵袭性NHL的疗效肯定,骨髓毒性较DICE方案为轻,是侵袭性NHL患者安全有效的解救治疗方案.     

Phase I/II study of galiximab, an anti-CD80 antibody, for relapsed or refractory follicular lymphoma.

PURPOSE: This multicenter, dose-escalation study evaluates the safety, pharmacokinetics, and efficacy of galiximab (anti-CD80 monoclonal antibody) in patients with relapsed or refractory follicular lymphoma. PATIENTS AND METHODS: Patients had follicular lymphoma that had relapsed or failed to respond to primary therapy; the majority (90%) presented with stage III or IV disease. Four weekly intravenous infusions of galiximab were administered at doses of 125, 250, 375, or 500 mg/m2. RESULTS: Thirty-seven patients received galiximab treatment and were evaluated for safety; 35 were assessable for response. Antibody infusions were safe and well tolerated with no dose-limiting toxicities. A total of 22 (60%) of 37 patients experienced adverse events related to galiximab. All but one of the events were grade 1 or 2; the most common were fatigue, nausea, and headache. Cytopenias were rare; only one patient experienced anemia and febrile neutropenia, which were unrelated to galiximab and resolved after treatment. No patient developed antigaliximab antibody formation. The mean serum half-life ranged from 13 to 24 days. The overall response rate was 11% (two complete responses and two partial responses). Time to best response was delayed (months 3, 6, 9, and 12). Twelve patients (34%) maintained stable disease. Nearly half of all patients (49%) had a decrease in indicator lesions. Two responders remain on study without progression (22 and 24.4 months). CONCLUSION: The favorable safety profile of galiximab and evidence of single-agent biologic activity and dose-dependent pharmacokinetics support further evaluation of galiximab as a treatment for follicular lymphoma, possibly in combination with other lymphoma therapies.     

Phase I/II study of bevacizumab with BKM120, an oral PI3K inhibitor,in patients with refractory solid tumors (phase I) and relapsed/refractory glioblastoma (phase II)

Journal of Neuro-Oncology - The brain is a very soft tissue. Glioblastoma (GBM) brain tumours are highly infiltrative into the surrounding healthy brain tissue and invasion mechanisms that have...     

Phase II study of tazemetostat for relapsed or refractory B-cell non-Hodgkin lymphoma with EZH2 mutation in Japan

Tazemetostat is a selective, reversible, small-molecule inhibitor of the histone methyltransferase enzyme, enhancer of zest homolog 2 (EZH2). In this multicenter, open-label, phase II study, we assessed the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma harboring the EZH2 mutation. Tazemetostat (800 mg twice daily) was given orally (28-day cycle) until disease progression or unacceptable toxicity. Among the 20 eligible patients, 17 were enrolled in cohort 1 (follicular lymphoma [FL]), and three were enrolled in cohort 2 (diffuse large B-cell lymphoma). At data cut-off, the objective response rate in cohort 1 was 76.5%, including six patients (35.3%) with complete response and seven patients (41.2%) with partial response (PR). All three patients in cohort 2 achieved PR. In cohort 1, median progression-free survival (PFS) was not reached at the median follow-up of 12.9 months. The estimated PFS rate at 12 and 15 months was 94.1% and 73.2%, respectively. The most common grade 3 treatment-emergent adverse event (TEAE) was lymphopenia (n = 2). Grade 4 TEAEs included hypertriglyceridemia and pneumonia aspiration (n = 1 each), which were not related to tazemetostat. Treatment-emergent adverse events leading to study drug discontinuation were reported in four of the 20 patients, indicating that the safety profile of tazemetostat was acceptable and manageable. Tazemetostat 800 mg twice daily showed encouraging efficacy in patients with R/R EZH2 mutation-positive FL with a manageable safety profile in the overall population. Thus, tazemetostat could be a potential treatment for R/R EZH2 mutation-positive FL.     

Phase 1 study of tazemetostat in Japanese patients with relapsed or refractory B-cell lymphoma

BackgroundTazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B‐cell non‐Hodgkin‐type lymphoma (B‐NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity.MethodsTazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28‐day/cycle manner. Tazemetostat dose‐limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations.ResultsAs of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B‐cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59‐85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment‐related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment‐related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment.ConclusionsTazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B‐NHL.     

Phase II study of PEND chemotherapy in patients with refractory/relapsed Hodgkin lymphoma

High-dose chemotherapy with autologous marrow or stem cell rescue (HDC/ASCT) is an effective strategy in patients with relapsed Hodgkin lymphoma. Various chemotherapy regimens have been used for cytoreduction prior to HDC/ASCT. In this study, our objective was to determine the response rate to PEND in a group of patients with relapsed Hodgkin lymphoma. Nineteen patients with relapsed or primary refractory Hodgkin lymphoma underwent treatment with the PEND regimen and received a median of 2 cycles (1 - 6 cycles). The PEND regimen builds on our prior results with ABDIC and consists of prednisone 40 mg/m² orally (PO) daily × 5 days; etoposide 50 mg/m² PO daily × 14 days; mitoxantrone 5 mg/m²/d IV, days 1 and 3; and DTIC 200 mg/m²/d intravenous continuous infusion (CIV) over 24 h, days 1 to 5, via central venous catheter. The treatment was given every 28 days. There were 3 complete responses (16%) and 10 partial responses (53%) yielding a total response rate of 69% (95% C.I. 43%, 87%). Myelosuppression was the predominant toxicity; no deaths were due to toxicity. After achieving maximum response to PEND, 10 eligible patients received a consolidative treatment with HDC/ASCT. All 6 patients who did not respond to PEND died from disease progression whereas 5 of 13 responders were alive after 10 years of follow-up (3 without disease). There were 11 deaths due to disease progression; three from other causes. The initial response to PEND before subsequent ASCT consolidation treatment appears to be associated with survival. All patients who failed to achieve a response have died. We conclude that PEND is an effective treatment strategy in Hodgkin lymphoma patients previously treated with both ABVD and MOPP.     

Multicenter phase II study of bendamustine for relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Bendamustine is a unique cytotoxic agent that has demonstrated efficacy in the treatment of indolent B‐cell non‐Hodgkin lymphomas (B‐NHLs). In this multicenter phase II trial, the efficacy and safety of bendamustine were evaluated in Japanese patients with relapsed or refractory indolent B‐NHL or mantle‐cell lymphoma (MCL). Patients received bendamustine (120 mg/m²) on days 1–2 of a 21‐day cycle, for up to six cycles. The primary endpoint was the overall response rate (ORR) as assessed by an extramural committee according to International Workshop Response Criteria (IWRC). Secondary endpoints included complete response (CR) rate, ORR according to Revised Response Criteria (revised RC), progression‐free survival (PFS), and safety. Fifty‐eight patients with indolent B‐NHL and 11 with MCL were enrolled. By IWRC, bendamustine produced an ORR of 91% (95% confidence interval [CI], 82–97%; 90% and 100% in patients with indolent B‐NHL and MCL, respectively), with a CR rate of 67% (95% CI, 54–78%). ORR and CR rates according to revised RC were 93% (95% CI, 84–98%) and 57% (95% CI, 44–68%), respectively. After a median follow‐up of 12.6 months, median PFS had not been reached. Estimated PFS rates at 1 year were 70% and 90% among indolent B‐NHL and MCL patients, respectively. Bendamustine was generally well tolerated. Reversible myelosuppression, including grade 3/4 leukopenia (65%) and neutropenia (72%), was the most clinically significant toxicity observed. Common non‐hematologic toxicities included mild gastrointestinal events and fatigue. These results demonstrate the high efficacy and tolerability of single‐agent bendamustine in relapsed patients with indolent B‐NHL or MCL histologies. (ClinicalTrials.gov ID: NCT00612183). (Cancer Sci 2010;)     

Japanese phase II study of 90Y-ibritumomab tiuxetan in patients with relapsed or refractory indolent B-cell lymphoma

There is no data about the efficacy and safety of radioimmunotherapy with ⁹⁰Y-ibritumomab tiuxetan in patients with relapsed or refractory indolent B-cell lymphoma pretreated with rituximab-containing chemotherapy. We focused on this in a Japanese phase II study. Radioimmunotherapy with ⁹⁰Y-ibritumomab tiuxetan (11.1 and 14.8 MBq) was evaluated in patients with 100–149 × 10⁹ and >150 × 10⁹ platelets/L, respectively. The primary endpoint was the overall response rate. Forty patients were treated with ⁹⁰Y-ibritumomab tiuxetan (18 with 11.1 MBq/kg and 22 with 14.8 MBq/kg). Thirty-five patients (88%) had been pretreated with rituximab, including 27 (68%) pretreated with rituximab-containing chemotherapy. The overall response rate was 83% (33/40; 95% confidence interval, 67–93%), and the complete response rate was 68% (27/40; 95% confidence interval, 51–81%). The overall response rates in patients pretreated with rituximab-containing chemotherapy and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were 83% (19/23) and 94% (17/18), respectively. The median progression-free survival time of the 40 patients who received ⁹⁰Y-ibritumomab tiuxetan was 9.6 months. Toxicity was primarily hematological and mostly transient. No grade 4 non-hematological toxicity was observed. In conclusion, radioimmunotherapy with ⁹⁰Y-ibritumomab tiuxetan is safe and highly effective in patients with relapsed or refractory indolent B-cell lymphoma, including those pretreated with rituximab-containing chemotherapy. (ClinicalTrials.gov number NCT00220285) ( Cancer Sci 2009; 100: 158–164)     

Phase I and pharmacokinetic study of bendamustine hydrochloride in relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Bendamustine is a cytotoxic agent with a novel mechanism of action. This phase I, dose‐escalation study evaluated the safety, tolerability, efficacy, and pharmacokinetics of bendamustine in Japanese patients with relapsed/refractory indolent B‐cell non‐Hodgkin lymphoma (B‐NHL) or mantle cell lymphoma (MCL) without major organ dysfunction. Bendamustine 90 or 120 mg/m² (dose escalation) was administered intravenously over 60 min on days 1 and 2 every 3 weeks for up to three cycles. Nine patients (eight indolent B‐NHL and one MCL) received per‐protocol treatment, three at 90 mg/m² and six at 120 mg/m². No dose‐limiting toxicities were observed; thus, the maximum‐tolerated dose was not reached. Grade 3/4 hematologic toxicities were neutropenia (33%) and leukopenia (33%). Non‐hematologic toxicities were grade 1/2 and included gastrointestinal events and fatigue. Peak plasma concentrations of bendamustine occurred near the end of infusion in both dose groups and were equivalent to therapeutic concentrations observed in vitro. Bendamustine was rapidly eliminated, with a mean elimination half‐life (t_1/2) of 29 min. Plasma concentrations of active metabolites M3 and M4 were approximately 4 and <1% of the plasma concentration of the parent molecule, with t_1/2 of 42 and 33 min, respectively. Two unconfirmed complete responses and six partial responses were observed for an overall response rate (ORR) of 89%. The recommended dose for this schedule in phase II trials is 120 mg/m². The acceptable safety profile and high ORR warrant further investigation of bendamustine in relapsed or refractory indolent B‐NHL and MCL. (ClinicalTrials.gov ID: NCT00389051). (Cancer Sci 2010)     

Phase II study of concomitant chemoradiotherapy in bulky refractory or chemoresistant relapsed lymphomas

PURPOSE: To evaluate the local efficacy of concomitant chemoradiotherapy in patients with mostly refractory lymphoma. METHODS AND MATERIALS: Patients with refractory or chemoresistant-relapsed lymphoma and bulky life-threatening masses were included in this study. A split course of concomitant radiotherapy and chemotherapy (mostly cisplatin and etoposide) was delivered during a 6-week period. Weekly blood tests and a clinical examination using the Radiation Therapy Oncology Group guidelines were performed to assess acute toxicity. The tumor response was evaluated 1-3 months after treatment and at regular follow-up visits. RESULTS: We enrolled 21 patients in the study between January 1998 and April 2003. Of the 21 patients, 60% had disseminated disease with bulky tumor masses and 85% had refractory lymphoma, of which most had been treated with at least two different chemotherapy regimens before concomitant chemoradiotherapy. Seventy-five percent received regimens containing cisplatinum and etoposide. The median radiation dose was 40 Gy (range, 12-62.5 Gy). Grade 3-4 hematologic toxicity and mucositis was observed in 70% and 30% of cases respectively, without any deaths. The overall response and complete remission rate was 70% and 20%, respectively. The 1-year overall survival and local progression-free survival rate was 20.4% and 54%, respectively. Three patients with localized disease were still alive 16, 33, and 48 months after treatment. CONCLUSION: Concomitant chemoradiotherapy for refractory or chemoresistant-relapsed lymphoma induced high hematologic toxicity, but seemed adequate for controlling local bulky tumor masses. No toxicity-related death was observed.     

Long-term complete responses after 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma

We present the long-term results of 18 chemotherapy relapsed indolent (N = 12) or transformed (N = 6) NHL patients of a phase II anti-CD20 (131)I-tositumomab (Bexxar) therapy study. The biphasic therapy included two injections of 450 mg unlabelled antibody combined with (131)I-tositumomab once as dosimetric and once as therapeutic activity delivering 75 or 65 cGy whole-body radiation dose to patients with normal or reduced platelet counts, respectively. Two patients were not treated due to disease progression during dosimetry. The overall response rate was 81% in the 16 patients treated, including 50% CR/CRu and 31% PR. Median progression free survival of the 16 patients was 22.5 months. Median overall survival has not been reached after a median observation of 48 months. Median PFS of complete responders (CR/CRu) has not been reached and will be greater than 51 months. Short-term side effects were mainly haematological and transient. Among the relevant long-term side effects, one patient previously treated with CHOP chemotherapy died from secondary myelodysplasia. Four patients developed HAMA. In conclusion, (131)I-tositumomab RIT demonstrated durable responses especially in those patients who achieved a complete response. Six of eight CR/CRu are ongoing after 46-70 months.     

氟达拉滨联合吡柔比星治疗复发难治性惰性非霍奇金淋巴瘤

 目的　探讨FT（氟达拉滨及吡柔比星）方案治疗复发难治惰性非霍奇金淋巴瘤（NHL）的有效性和安全性。方法　复发难治惰性NHL40例,采用FT方案化疗,28 d为1个周期,共6个周期。FND（氟达拉滨、米托蒽醌及地塞米松）方案治疗惰性NHL的数据为对照。结果　FT组40例共治疗228个周期,有效率62.5 %,中位无进展生存期超过20个月,2年总生存率70.0 %,与对照组相似（P＞0.05）;不良反应以中性粒细胞减少（80.0 %）最为常见,但Ⅲ～Ⅳ度中性粒细胞减少症和肺炎的发生率均低于对照组,分别为12.5 %、29.0 %和2.5 %、23.0 %（P＜0.05）。结论　FT方案治疗复发难治惰性NHL安全有效,骨髓抑制轻,感染发生率低。     

A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma.

BACKGROUND: Protein kinase C beta (PKCbeta), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCbeta/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. PATIENTS AND METHODS: Patients with relapsed/refractory MCL, and no more than four regimens of prior therapy, received 500 mg enzastaurin, orally, once daily. RESULTS: Sixty patients, median age 66 years (range 45-85), Eastern Cooperative Oncology Group performance status of zero to two (48% had baseline International Prognostic Index of 3-5), were enrolled. Most patients had prior CHOP-like chemotherapy and/or rituximab (median = 2 regimens). No drug-related deaths occurred. There was one case each of grade 3 anemia, diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue was the most common toxicity. Although no objective tumor responses occurred, 22 patients (37%, 95% CI 25% to 49%) were free from progression (FFP) for > or =3 cycles (one cycle = 28 days); 6 of 22 were FFP for >6 months. Two patients remain on treatment and FFP at >23 months. CONCLUSION: Freedom from progression for >6 months in six patients and a favorable toxicity profile with minimal hematological toxicity indicate that enzastaurin warrants evaluation as maintenance therapy and combination chemotherapy in MCL.