Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma

Background: Rituximab is a chimeric monoclonal antibody directed against the B-cell CD20 antigen which has been utilized for therapy of B-cell non-Hodgkin's lymphoma. A previous clinical trial demonstrated that treatment with four weekly doses of 375 mg/m² of Rituximab in patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) was well tolerated and had significant clinical activity.Patients and methods: To assess the safety and efficacy of Rituximab treatment, an open-label, single-arm, multi-center, phase II study of eight consecutive weekly infusions of 375 mg/m² Rituximab in patients with low-grade or follicular B-cell NHL who had relapsed or had failed primary therapy was conducted. Thirty-seven patients with a median age of 55 years were treated.Results: Grade 1 or 2 adverse events were the majority of reported toxicities and occurred most frequently with the first infusion, decreasing with subsequent infusions. No patients developed a host antibody response (HACA) to Rituximab. The mean serum immunoglobulin levels for IgG, IgA, and IgM stayed within the normal range throughout the study. The majority of patients who were bcl-2 positive at baseline in peripheral blood became bcl-2 negative during treatment and remained negative at the time of B-cell recovery. In the 37 intent-to-treat patients, 5 (14%) had a complete response and 16 (43%) had a partial response for an overall response rate of 57%. Of 35 evaluable patients, 21 (60%) responded to treatment (14% CR and 46% PR). In responders, the median time to progression (TTP) and the median response duration have not been reached after 19.4+ months and 13.4+ months, respectively.Conclusions: The safety profile and efficacy achieved in this pilot study of extended treatment with Rituximab compares favorably with that seen with four weekly doses. Further studies are warranted to investigate whether this or other extended Rituximab schedules will result in increased efficacy in all or in certain subgroups of patients with low-grade or follicular NHL.     

Monoclonal antibodies for the treatment of hematologic malignancies: clinical trials in Japan

Of 12 patients with relapsed CD20(+) B-cell non-Hodgkin's lymphoma (B-NHL) enrolled in a phase I study of rituximab, 11 were eligible, and of these 2 achieved a complete response and 5 a partial response. The elimination half-life of rituximab was 445+/-361 h, and serum rituximab levels were detectable at 3 months. In a phase II study, 90 patients with relapsed indolent B-NHL or mantle cell lymphoma (MCL) were treated with infusions of rituximab 375 mg/m(2) once weekly for four doses. The overall response rate in indolent B-NHL and MCL was 61% (37/61, 95% CI 47-73%) and 46% (6/13, 95% CI 19-75%), respectively. The median progression-free survival (PFS) was shorter in MCL patients, in those with extranodal disease, and in those who had received two or more prior chemotherapy regimens ( P<0.01). Rituximab retreatment was well tolerated in 13 patients with relapsed indolent B-NHL and there were no grade 3/4 nonhematologic toxicities. Partial response was observed in five (38%, 95% CI 14-68%) patients, and the median PFS after retreatment was 5.1 months. In a single-agent phase II study of infusions of rituximab 375 mg/m(2) once weekly for eight doses against relapsed aggressive B-NHL showed, 21 (37%, 95% CI 24-51%) of the 57 eligible patients responded. In conclusion, rituximab is a highly effective agent in relapsed indolent and aggressive B-NHL and MCL with acceptable toxicities. Yttrium-90 provides advantages over iodine-131 because it delivers higher beta energy. In 2002, we initiated a feasibility study of yttrium-90-labeled ibritumomab tiuxetan for relapsed indolent B-NHL in Japan. Gemtuzumab ozogamicin (CMA-676) is a calicheamicin-conjugated humanized anti-CD33 monoclonal antibody. Of 20 patients with relapsed or refractory acute myeloid leukemia enrolled in a "bridging" phase I/II study, 7 showed an objective response. It is concluded that monoclonal antibodies will have play a significant role in the treatment of hematologic malignancies in the future.     

Factors affecting toxicity, response and progression-free survival in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma treated with rituximab: a Japanese phase II study.

BACKGROUND: The aim of the study was to determine factors affecting the toxicity and efficacy of rituximab monotherapy in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma (MCL). PATIENTS AND METHODS: A total of 90 patients were enrolled and treated with rituximab infusions at 375 mg/m2 once weekly for 4 weeks. Central pathology review revealed that histologically, 81 patients had indolent B-cell lymphoma or MCL: 59 with follicular lymphoma, 17 with MCL, four with marginal zone lymphoma and one with lymphoplasmacytoid lymphoma. Of these, four were ineligible due to violation of other eligibility criteria. Pre-treatment variables affecting toxicities were analyzed for all 90 patients, and those affecting response and progression-free survival (PFS) were analyzed for 77 eligible patients with confirmed indolent B-cell lymphoma or MCL. The relationship between serum rituximab levels and efficacy was also analyzed for 66 eligible patients. RESULTS: Hematological toxicities (grade > or =3) occurred more frequently in females (P <0.05), and thrombocytopenia and leukopenia were more frequent in patients with high lactate dehydrogenase (LDH) levels (P <0.05). Non-hematological toxicities (grade > or =2) were more frequent in patients with extranodal disease or bone marrow involvement. The overall response rate (ORR) in patients receiving one prior chemotherapy regimen was higher than those receiving two or more regimens (P <0.05). The median PFS was shorter in MCL patients, in those with extranodal disease, or in those receiving two or more prior chemotherapy regimens (P <0.01). The PFS intervals of patients with higher serum rituximab levels (> or =70 microg/ml) immediately before the third infusion were longer than in other patients (P <0.01). CONCLUSIONS: Several prognostic factors and serum rituximab levels are useful for predicting the toxicity and efficacy of rituximab monotherapy.     

Salvage therapy for relapsed mediastinal B-cell lymphoma with allogeneic HLA-identical related donor bone marrow transplantation, donor lymphocyte infusion and IDEC-C2B8.

Primary B-cell lymphoma of the mediastinum is an aggressive non-Hodgkin's lymphoma with distinct clinicopathologic features. Response rates are between 60-80% following intensive chemotherapy regimens. Poor responders or patients with an early relapse usually do not achieve a prolonged second remission with conventional salvage therapy protocols and therefore qualify for intensive or experimental approaches. Here we describe two patients of same age, gender and stage with primary mediastinal B-cell lymphoma and an early relapse after the first courses of combination chemotherapy and irradiation of the mediastinum. One patient relapsed after a salvage therapy with allogeneic donor-related bone marrow transplantation and donor lymphocyte infusion but responded again with a continuing good partial remission after infusion of the chimeric anti-CD20 antibody IDEC-C2B8. For the other patient an allogeneic bone marrow transplantation was not possible. He finally failed to respond to salvage therapy with IDEC-C2B8 and died of progressive disease. The anti-CD20 antibody IDEC-C2B8 induced a partial remission in a patient with primary mediastinal B-cell lymphoma refractory to other therapeutic approaches, including allogeneic bone marrow transplanatation (alloBMT), donor lymphocyte infusion (DLI) and irradiation. The role of IDEC-C2B8 as a component of salvage regimens appears to be worthy for further evaluation in high-risk patients with primary mediastinal B-cell lymphoma     

Salvage Therapy for Relapsed Mediastinal B-Cell Lymphoma with Allogeneic HLA-Identical Related Donor Bone Marrow Transplantation, Donor Lymphocyte Infusion and IDEC-C2B8

Primary B-cell lymphoma of the mediastinum is an aggressive non-Hodgkin's lymphoma with distinct clinicopathologic features. Response rates are between 60-80% following intensive chemotherapy regimens. Poor responders or patients with an early relapse usually do not achieve a prolonged second remission with conventional salvage therapy protocols and therefore qualify for intensive or experimental approaches. Here we describe two patients of same age, gender and stage with primary mediastinal B-cell lymphoma and an early relapse after the first courses of combination chemotherapy and irradiation of the mediastinum. One patient relapsed after a salvage therapy with allogeneic donor-related bone marrow transplantation and donor lymphocyte infusion but responded again with a continuing good partial remission after infusion of the chimeric anti-CD20 antibody IDEC-C2B8. For the other patient an allogeneic bone marrow transplantation was not possible. He finally failed to respond to salvage therapy with IDEC-C2B8 and died of progressive disease. The anti-CD20 antibody IDEC-C2B8 induced a partial remission in a patient with primary mediastinal B-cell lymphoma refractory to other therapeutic approaches, including allogeneic bone marrow transplanatation (alloBMT), donor lymphocyte infusion (DLI) and irradiation. The role of IDEC-C2B8 as a component of salvage regimens appears to be worthy for further evaluation in high-risk patients with primary mediastinal B-cell lymphoma     

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.     

Combination chemotherapy with irinotecan and adriamycin for refractory and relapsed non-Hodgkin's lymphoma

Twenty-five patients with relapsed or refractory non-Hodgkin's lymphomawere treated by combination chemotherapy with irinotecan hydrochloride(CPT-11) and adriamycin (ADM): CPT-11, 25 mg/m² on days 1 and 2;ADM, 40 mg/m² on day 3. Nine (36%) of twenty-five patientsachieved CR. Fairly good responses were seen in relapsed B-cell lymphomas (4of 8 in diffuse large B-cell lymphoma and 2 of 2 in follicular lymphoma grade1), and substantial responses in T-cell lymphomas (1 of 4 in peripheral T-celllymphoma and 2 of 7 in adult T-cell leukemia/lymphoma). Leukopenia wasfrequent but tolerable, and diarrhea minimal. Combination chemotherapy witha reduced dose CPT-11 and ADM was useful in the treatment of relapsednon-Hodgkin's lymphoma.     

Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin lymphoma and despite recent chemotherapeutic advances up to half of all patients relapse. Here we report the results from a phase 2, single-arm, single-center trial evaluating the safety and efficacy of lenalidomide plus rituximab in elderly patients with relapsed or refractory DLBCL.Patients and MethodsBetween March and June 2009, elderly patients (65 years of age or older) with relapsed/refractory DLBCL who had been heavily pretreated were recruited. Oral lenalidomide (20 mg/d for 21 days of each 28-day cycle) was initiated for four cycles and rituximab (375 mg/m²) was administered on day 1 and day 21 of each 28-day cycle for four cycles. After this induction phase, patients achieving a complete response (CR), partial response (PR), or stable disease (SD) were given lenalidomide maintenance therapy at the same schedule for another 8 months.ResultsA total of 23 patients with a median of three prior treatments (range, 2 to 8) were included. The overall response rate (CR + PR) at the end of the induction phase was 35% (n = 8). Ten patients (7 CR, 1 PR, and 2 SD patients) were eligible for lenalidomide maintenance and 8 of these patients achieved a CR. Adverse events were manageable and the most common included neutropenia and thrombocytopenia.ConclusionOral lenalidomide in combination with rituximab is active in elderly patients with relapsed/refractory DLBCL with a high percentage of patients achieving a continuous CR after lenalidomide maintenance.     

Phase I/II and pharmacokinetic study of cladribine with 2-h infusion in Japanese patients with relapsed indolent B-cell lymphoma mostly pretreated with rituximab

We conducted a phase I/II study to investigate the toxicity, pharmacokinetics, and efficacy profiles of cladribine with 2-h intravenous infusion for five consecutive days every four weeks in Japanese patients with relapsed indolent B-cell lymphoma. This was a dose-escalation study to confirm the safety of the doses which have been recommended for Caucasian patients (phase I), and to further evaluate the efficacy and safety (phase II). In the phase I portion for nine patients, no dose-limiting toxicities were observed at levels 1 (0.09 mg/kg/day, n  = 3) and 2 (0.12 mg/kg/day, n  = 6). No appreciable accumulation of plasma cladribine concentration was suggested. We enrolled a total of 20 patients, and an additional 14 patients in the phase II portion at level 2 (0.12 mg/kg/day). Eighteen patients, including 13 with follicular lymphoma, were eligible for efficacy evaluation, and 15 (83%) were pretreated with rituximab. The overall response rate was 50% (9/18; 80% confidence interval, 35–65%), with 11% (2/18) complete response. With a median follow-up of 296 days, the estimated median time to progression for 18 eligible patients was 382 days. The most frequent adverse events were hematologic toxicities, including grade 4 neutropenia. Non-hematologic toxicities were mild. In conclusion, cladribine with 2-h intravenous infusion for five consecutive days every four weeks is effective with acceptable toxicities for Japanese patients with relapsed indolent B-cell lymphoma, including those pretreated with rituximab. ( Cancer Sci 2009; 100: 1344–1350)     

Results of a phase I/II study of ocrelizumab,a fully humanized anti-CD20 mAb,in patients with relapsed/refractory follicular lymphoma

BackgroundOcrelizumab is a humanized anti-CD20 antibody with increased antibody-dependent cellular cytotoxicity compared with rituximab. This phase I/II study evaluated its safety and efficacy in patients with relapsed/refractory follicular lymphoma (FL) after prior rituximab therapy.Design and methodsForty-seven patients were treated in three dose cohorts and received eight infusions every 3 weeks: cohort A, 200 mg/m² (n = 15); cohort B, 375 mg/m² (n = 16); cohort C, first dose 375 mg/m², seven subsequent doses of 750 mg/m² (n = 16). Patients were assessed for safety, efficacy, pharmacodynamics and pharmacokinetics.ResultsThe median patient age was 58 years, the majority had Ann Arbor stage III/IV disease and had received a median of 2 (range 1–6) prior regimens. Ocrelizumab was well tolerated with grade 3/4 toxicity occurring in 9% of patients. The most common toxicity was infusion-related reactions (74% patients), all grade 1/2 except one grade 3 event. The objective response rate was 38% and was similar in patients with low-affinity and high-affinity variants of the Fcγ receptor IIIa (FcγRIIIa). With follow-up of ∼28 months, the median progression-free survival was 11.4 months.ConclusionOcrelizumab demonstrated activity in patients with relapsed/refractory FL following prior rituximab treatment, with safety similar to rituximab although adverse events appeared milder.     

A multicenter,phase II study of R-THP-COP therapy for elderly patients with newly diagnosed,advanced-stage,indolent B-cell lymphoma

The optimal combined chemotherapy regimen with rituximab has yet to be established for elderly patients with advanced-stage indolent B-cell lymphoma (B-NHL). A multicenter study was performed to evaluate the efficacy and toxicity of R-THP-COP therapy in elderly patients (aged 70–79 years) with newly diagnosed advanced-stage indolent B-NHL using the complete response rate (%CR) as the primary endpoint. Patients with newly diagnosed, clinical stage III/IV, indolent B-NHL, aged 70–79 years, with a performance status of 0–2 were eligible for this study. R-THP-COP consists of 375 mg/m² of rituximab, 50 mg/m² of pirarubicin, 750 mg/m² of cyclophosphamide, 1.4 mg/m² of vincristine, and 100 mg/day of oral prednisolone for 5 days. This study was discontinued due to poor accrual after the enrollment of 18 patients, although the planned sample size was 40 patients. The numbers of patients with follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, and mantle cell lymphoma were 16, 1, and 1, respectively. The median age was 73 (range, 70 to 79) years. The %CR including unconfirmed CR was 45% (95% confidence interval: 25-66%) and the overall response rate was 72%. The estimated 5-year overall survival and progression-free survival rates were 55% and 28%, respectively. The major toxicity observed was grade 4 neutropenia (94%). Grade 4 non-hematological toxicities were not observed and no patients developed grade 3/4 cardiac toxicities. This phase II study provides useful information regarding the efficacy and toxicity of R-THP-COP therapy for patients aged 70 years or older with newly diagnosed, advanced-stage, indolent B-NHL, although the sample size was small.     

Spotlight on Rituximab in Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin’s lymphoma (NHL) and B-cell chronic lymphocytic leukemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m² intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomized comparison of eight cycles of CHOP plus rituximab 375 mg/m² intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse hematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities. Conclusion: Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced hematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs.     

Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy.

BACKGROUND: High-dose therapy (HDT) with stem-cell support is the reference treatment for relapsed lymphoma, but is not appropriate for all patients. Conventional salvage chemotherapies have been used with limited efficacy and significant toxicity. Rituximab, gemcitabine and oxaliplatin are active as single agents in relapsed or refractory lymphoma, and have demonstrated synergistic effects in vitro and in vivo. PATIENTS AND METHODS: Forty-six patients with relapsed or refractory B-cell lymphoma received up to eight cycles of R-GemOx (rituximab 375 mg/m(2) on day 1, gemcitabine 1000 mg/m(2) and oxaliplatin 100 mg/m(2) on day 2). The majority (72%) had diffuse large B-cell lymphoma. RESULTS: After four cycles of R-GemOx, the overall response rate was 83% [50% complete response (CR)/unconfirmed CR (CRu)]. High CR/CRu rates were observed in all histological subtypes. In patients who had previously received rituximab, the CR/CRu rate after eight cycles was 65%. The 2-year event-free and overall survival rates (median follow-up of 28 months) were 43% and 66%, respectively. Among responders, the probability of being disease free for 2 years was 62%. Treatment was generally well tolerated. CONCLUSION: R-GemOx shows promising activity with acceptable toxicity in patients with relapsed/refractory B-cell lymphoma who are not eligible for HDT.     

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 I study of inotuzumab ozogamicin (CMC‐544) in Japanese patients with follicular lymphoma pretreated with rituximab‐based therapy

Inotuzumab ozogamicin (CMC‐544), an antibody‐targeted chemotherapeutic agent composed of an anti‐CD22 antibody conjugated to calicheamicin, a potent cytotoxic antibiotic, specifically targets the CD22 antigen present in >90% of B‐lymphoid malignancies, rendering it useful for treating patients with B‐cell non‐Hodgkin lymphoma (B‐NHL). This phase I study evaluated the safety, tolerability, efficacy, and pharmacokinetics of inotuzumab ozogamicin in Japanese patients. Eligible patients had relapsed or refractory CD22‐positive B‐NHL without major organ dysfunction. Inotuzumab ozogamicin was administered intravenously once every 28 days (dose escalation: 1.3 and 1.8 mg/m²). All 13 patients had follicular lymphoma, were previously treated with ≥1 rituximab‐alone or rituximab‐containing chemotherapy, and were enrolled into two dose cohorts (1.3 mg/m², three patients; 1.8 mg/m², 10 patients). No patient had dose‐limiting toxicities, and the maximum tolerated dose, previously determined in non‐Japanese patients (1.8 mg/m²), was confirmed. Drug‐related adverse events (AEs) included thrombocytopenia (100%), leukopenia (92%), lymphopenia (85%), neutropenia (85%), elevated AST (85%), anorexia (85%), and nausea (77%). Grade 3/4 drug‐related AEs in ≥15% patients were thrombocytopenia (54%), lymphopenia (31%), neutropenia (31%), and leukopenia (15%). The AUC and C_max of inotuzumab ozogamicin increased dose‐dependently with pharmacokinetic profiles similar to non‐Japanese. Seven patients had complete response (CR, 54%) including unconfirmed CR, four patients had partial response (31%), and two patients had stable disease (15%). The overall response rate was 85% (11/13). Inotuzumab ozogamicin was well tolerated at doses up to 1.8 mg/m² and showed preliminary evidence of activity in relapsed or refractory follicular lymphoma pretreated with rituximab‐containing therapy, warranting further investigations. This trial was registered in ClinicalTrials.gov (NCT00717925). (Cancer Sci 2010)     

利妥昔单抗联合CHOP方案治疗B细胞非霍奇金淋巴瘤的临床分析

目的 观察利妥昔单抗联合CHOP方案治疗CD20阳性B细胞非霍奇金淋巴瘤的临床疗效及毒副反应.方法 8例B细胞非霍奇金淋巴瘤均采用利妥昔单抗联合化疗,利妥昔单抗375 ms/m2于每1周期化疗前1天静脉滴注,每3周为1疗程,4～6周期后评价疗效及毒副反应.结果 8例患者中,CR 7例,PR 1例,总有效率100%.主要...     

A phase I study using bortezomib with weekly idarubicin for treatment of elderly patients with acute myeloid leukemia

We report the results of a phase I study with four dose levels of bortezomib in combination with idarubicin. Eligible patients were newly diagnosed with acute myeloid leukemia (AML) age ≥60 years, or any adult with relapsed AML. Bortezomib was given twice weekly at 0.8, 1.0, or 1.2 mg/m² with once weekly idarubicin 10 mg/m² for four weeks. Twenty patients were treated: 13 newly diagnosed (median age 68, range 61–83) and 7 relapsed (median age 58, range 40–77). Prior myelodysplastic syndrome (MDS) was documented in 10/13 (77%) newly diagnosed and 1/7 (14%) relapsed patients; the three newly diagnosed patients without prior MDS had dyspoietic morphology. Two dose-limiting toxicities occurred at the initial dose level (bortezomib 0.8 mg/m² and idarubicin 10 mg/m²); idarubicin was reduced to 8 mg/m² without observing subsequent dose-limiting toxicities. The maximum tolerated dose in this study was bortezomib 1.2 mg/m² and idarubicin 8 mg/m². Common adverse events included: neutropenic fever, infections, constitutional symptoms, and gastrointestinal symptoms. No subjects experienced neurotoxicity. Most patients demonstrated hematologic response as evidenced by decreased circulating blasts. Four patients (20%) achieved complete remission. There was one treatment-related death. The combination of bortezomib and idarubicin in this mostly poor-risk, older AML group was well tolerated and did not result in high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00382954.     

Combination Phase I/II Study of Irinotecan Hydrochloride (CPT-11) and Carboplatin in Relapsed or Refractory Non-Hodgkin's Lymphoma

Irinotecan hydrochloride (CPT-11) is a new derivative of camptothecinwhich inhibits topoisomerase I. Phase II studies have demonstratedthat CPT-11 is active against a broad spectrum of neoplasmsincluding intractable non-Hodgkin's lymphoma. An early phaseII study in lymphoma suggested that a schedule of daily infusionsof 40 mg/m²/day for three or five consecutive days is more effectivethan a single infusion of 200 mg/m² every three to four weeks.Carboplatin is also an active agent against lymphoma, and preclinicalstudies have shown that CPT-11 and its active metabolite havea synergistic effect with platinum compounds. To evaluate themaximal tolerated dose (MTD) and the therapeutic efficacy ofCPT-11 in combination with carboplatin in relapsed or refractorynon-Hodgkin's lymphoma, we conducted a combination phase I/IIstudy. The starting dose of CPT-11 was 20 mg/m²/day (days 1through 3 and 8 through 10), and dose escalations of 5 mg/m²/dayincrements were planned, with a fixed dose of carboplatin (300mg/m², day 1). Six of the eight patients receiving both agentsat the starting dose level developed critical toxicities suchas grade 4 hematologic (neutropenia 6/8, thrombocytopenia 1/8)and grade 3 non-hematologic toxicities (diarrhea 2/8, transaminaseelevation 1/8). Further dose escalation of CPT-11 was halted,and the starting doses were judged to be the MTDs. The responserate (25%, 2/8) to the combination of the MTDs was not superiorto that of CPT-11 alone in a previous phase II study (38%, 26/69),and the MTD of CPT-11 in combination with carboplatin was lessthan half the single-agent dose. We conclude that carboplatinis not recommendable for combination with CPT-11 in lymphomapatients. Other suitable agents for such a combination shouldbe sought.     

Excellent Tolerance of Rituximab When Given After Mitoxantrone/Cyclophosphamide: An Effective and Safe Combination for Indolent Non-Hodgkin's Lymphoma

Treatment for extensive indolent lymphoma should provide optimization of efficacy while avoiding excessive toxicity. Rituximab may be an ideal agent to combine with chemotherapy because of its lack of classical myelotoxicity. In this study, 27 patients with a variety of histologies of indolent B-cell non-Hodgkin's lymphoma have been treated utilizing a novel three-drug combination. Nine patients had relapsed disease and 18 were previously untreated. Patients first received cyclophosphamide 800 mg/m² and mitoxantrone 8 mg/m² I.V. on day 1, every 3 weeks for 2 cycles. Subsequently, patients received rituximab 375 mg/m² followed by mitoxantrone 8 mg/m² every 2 weeks for 4 cycles. This regimen and, in particular, the rituximab infusion were extremely well tolerated. Only two of 27 patients experienced a grade 1/2, infusion-related reaction during the first rituximab infusion. Grade 4 neutropenia was noted at some point in 16 patients who were then offered granulocyte-macrophage colony-stimulating factor support for improvement of neutropenia. No infections were noted. Alopecia was minimal. Of 27 patients, 19 achieved a complete response (CR), one achieved an unconfirmed CR (CRu), and five patients achieved a partial response, for an overall response rate of 92.5%. Molecular remissions were noted in seven of 12 tested patients in CR. We concluded that the cyclophosphamide/mitoxantrone/rituximab (CyMiR) regimen is effective and extremely well tolerated. Furthermore, rituximab infusion-associated morbidity is markedly reduced .     

Experience with 9-Cis Retinoic Acid in Patients with Relapsed and Refractory Non-Hodgkin's Lymphoma

We conducted a phase II study to determine the efficacy and toxicity of 9-cis-retinoic acid (9-cis RA), a pan-retinoid receptor agonist, in the treatment of patients with relapsed and refractory NHL. Patients were eligible if they had histologically documented relapsed or refractory T cell or indolent B cell NHL. The first three patients enrolled received 70 mg/m² of 9-cis RA orally twice a day, but the remaining patients received a single oral daily dose of 100 mg/m². After 6 weeks of therapy, tumor response was assessed objectively. Response rate and toxicity were determined in all 29 eligible patients based on an intent-to-treat analysis. Four patients (14%) responded (3 PRs and 1 CR; 95% CI 4%- 33%). One patient had a minor response, and eight had stable disease. Responses were observed in two (11%) of 19 patients with B-cell lymphoma and in two (20%) of 10 patients with T-cell lymphoma. The median time-to-treatment failure for the 29 eligible patients was 8 weeks. The most frequent toxic effects were dry skin, headache, hypertriglyceridemia, and hypercalcemia. Five patients discontinued therapy due to toxic side effects, but no toxic deaths occurred during the study. We conclude that 9-cis RA has a modest activity in relapsed and refractory NHL. In this study, responses were observed in patients with B-cell lymphomas and those with T-cell lymphomas.