Clinical Observation of FMD Regimen:Fludarabine,Mitoxantrone, Dexamethasone, in Treatment of Non-Hodgkin''s Lymphoma

Objective  To evaluate the clinical effectivity and toxicity of the regimen FMD (fludarabine, mitoxantrone, dexamethasone) in patients with non-Hodgkin’s lymphoma. Methods  Thirty-two patients, twenty-four of whom had indolent B-cell lymphoma, 6 peripheral T-cell lymphoma, two diffuse large B-cell lymphoma, received FMD. Treatment comprised: fludarabine 25∼30 mg/m² days 1∼3, mitoxantrone 8∼10 mg/m² day 1, and dexamethasone 20∼30 mg/m² days 1∼5. At the same time, patients received prophylaxis against conditional infection with trimethoprim-sulfamethoxazole, fluconazole, acyclovir and immunoglobulin. Results  Of the thirty-two patients treated, the complete response (CR) rate, partial response (PR) rate and overall response (OR) rate were 56.3%, 21.9% and 78.2% respectively. The CR and OR rate of 24 patients with indolent B-cell lymphoma were 66.7% and 88.3% respectively. Two of six patients with peripheral T-cell lymphoma were of complete response type and one was of partial response type. One of two patients with diffuse large B-cell lymphoma was partial response. The dominating toxicity was myelotoxicity and immunotoxicity. There was no treatment associated death in all patients treated with FMD. Grade 3∼4 neutropenia occurred in 43.8% patients, 12.5% patients had infections and 9.3% developed grade 3∼4 thrombocytopenia. At a median follow-up of 24 (5∼54) months, the 2-year overall-survival rate and progression-free survival rate were (87.5 ± 1.4)% and (83.3 ± 1.6)% respectively. The 2-year OS and PFS rates of the indolent group were (93.75 ± 6.25)% and (87.5 ± 8.54)%. Conclusion  FMD regimen was highly effective with low toxicity in the treatment of non-Hodgkin’s lymphoma, especially in indolent B-cell lymphoma. It also helps to improve the prognosis even in some aggressive lymphoma, such as peripheral T cell lymphoma.     

Loss of CD20 antigen expression after rituximab therapy of CD20 positive B cell lymphoma (diffuse large B cell extranodal marginal zone lymphoma combination): A case report and review of the literature

Rituximab (the chimeric anti-CD20 antibody) is widely used in the treatment of CD20 positive non-Hodgkin’s lymphoma (NHL). The response rate at relapse after repeated use in prior CD20 positive responders is lower than 50%. Several mechanisms can be responsible for rituximab resistance. CD20 negative relapses which transformed from CD20 positive aggressive and indolent forms of lymphoma can be the one of the reason of secondary resistance to rituximab. The authors report a case with combination of aggressive and indolent form of lymphoma who relapsed after 7 months from the last dose of rituximab therapy. CD20 transformed negative from positive in her relapsed disease. Patients with CD20 positive B cell NHL must rebiopsy after first line rituximab therapy if their disease relapsed or progressed.     

Combination antibody therapy with epratuzumab and rituximab in relapsed or refractory non-Hodgkin's lymphoma.

PURPOSE: To explore the safety and therapeutic activity of combination anti-B-cell monoclonal antibody therapy in non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Twenty-three patients with recurrent B-cell lymphoma received anti-CD22 epratuzumab 360 mg/m(2) and anti-CD20 rituximab 375 mg/m(2) monoclonal antibodies weekly for four doses each. Sixteen patients had indolent histologies (15 with follicular lymphoma) and seven had aggressive NHL (all diffuse large B-cell lymphoma [DLBCL]). Indolent patients had received a median of one (range, one to six) prior treatment, with 31% refractory to their last therapy and 81% with high-risk Follicular Lymphoma International Prognostic Index scores. Patients with DLBCL had a median of three (range, one to eight) prior regimens (14% resistant to last treatment) and 71% had high intermediate-risk or high-risk International Prognostic Index scores. All patients were rituximab na?ve. RESULTS: Treatment was well tolerated, with toxicities principally infusion-related and predominantly grade 1 or 2. Ten (67%) patients with follicular NHL achieved an objective response (OR), including nine of 15 (60%) with complete responses (CRs and unconfirmed CRs). Four of six assessable patients (67%) with DLBCL achieved an OR, including three (50%) CRs. Median time to progression for all indolent NHL patients was 17.8 months. CONCLUSION: The full-dose combination of epratuzumab with rituximab was well tolerated and had significant clinical activity in NHL, suggesting that this combination should be tested in comparison with single-agent treatment.     

Liposomal daunorubicin in the treatment of relapsed or refractory non-Hodgkin''s lymphoma.

Purpose:To assess the efficacy and toxicity of liposomal daunorubicin administered as a two-hour intravenous infusion to patients with relapsed or refractory non-Hodgkins lymphoma (NHL). Patients and methods:Eligible patients had relapsed or refractory NHL with measurable or evaluable disease, and low grade, select intermediate grade, or mantle cell pathologic types. Prior exposure to an anthracycline or anthracenedione was allowed. Liposomal daunorubicin at a dose of 100 mg/m² was given intravenously over a minimum of 120 minutes every 3 weeks, as a single agent. Results:Thirty-three patients were accrued: twenty-three (70%) had low-grade histologies; six (18%) had intermediate-grade histologies (follicular large-cell and diffuse small cleaved); and four (12%) patients had mantle-cell lymphoma. Eighteen (55%) had received two or more prior regimens; fourteen (42%) received a prior anthracycline. A median of six cycles of liposomal daunorubicin were administered (range 1–15). Of 31 patients evaluable for response, 2 complete and 10 partial remissions were documented for a major response rate of 39% (95% confidence interval (CI): 22%–58%). The median duration of response was 19.5 months (range 4.3–41.1+). Six responders (50%) had received a prior anthracycline; one responder had mantle-cell histology. The major toxicities were grade 3 or 4 neutropenia in 26 patients (79%), mild to moderate nausea in 22 (67%), and fatigue in 16 (48%). Conclusions:Liposomal daunorubicin at 100 mg/m² every three weeks has activity in patients with relapsed or refractory NHL, including patients with prior exposure to an anthracycline. Further studies of liposomal daunorubicin in combination with other agents are warranted.     

VEDex (vincristine, epirubicin dexamethasone): an effective and well tolerated palliative chemotherapy regimen for non-Hodgkin's lymphoma

An evaluation was carried out of the efficacy and toxicity of a novel weekly palliative chemotherapy regimen comprising vincristine, epirubicin and dexamethasone (VEDex) in 57 patients with non-Hodgkin's lymphoma (NHL) treated at this centre. The age range was 34-88 years and the median age was 67 years. Twenty-three patients (40%) had low grade disease and 4 patients (7%) had transformed NHL. Thirty patients (53%) had high grade NHL; 7 had relapsed after conventional chemotherapy and were not fit for high-dose chemotherapy, 7 were heavily pre-treated, 8 had received prior radiotherapy and 8 had not received any prior therapy. Responding patients received a total of 8 weeks of treatment, but treatment could be repeated at a later stage if required. The overall response rate was 66.6%; 11 patients (19.3%) achieved a complete response and 27 (47.3%) achieved a partial response. A further 11 patients (19.3%) had stable disease. Twenty-four patients (42.1%) reported complete resolution of symptoms and 21 (36.8%) had partial resolution of symptoms. The median survival from the onset of treatment was 6 months. Grade III neutropenia was seen in 9 patients (15.8%). Other toxicity included nausea and vomiting grade II (3.5%), grade III (1.8%) and alopecia grade III (1.8%). There were no treatment related deaths. We conclude that VEDex is an effective palliative treatment in patients with indolent or aggressive lymphoma with poor performance status or who have been heavily pre-treated. It is well tolerated in the elderly.     

A multicenter phase II trial of etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin for patients with primary refractory/relapsed aggressive non-Hodgkin’s lymphoma

Purpose  We investigated the efficacy and toxicity of the etoposide, methylprednisolone, high-dose cytarabine, and oxaliplatin (ESHAOx), in which oxaliplatin (Ox) was substituted for cisplatin in the ESHAP [etoposide (E), methylprednisolone (S), high-dose cytarabine (HA), and cisplatin (P)] regimen, for patients with refractory/relapsed aggressive non-Hodgkin’s lymphoma (NHL). Materials and methods  The ESHAOx consisted of E (40 mg/m² on days 1–4), S (500 mg on days 1–5), HA (2 g/m² on day 5), and Ox (130 mg/m² on day 1) every 3 weeks to a maximum of six cycles. Responses were assessed every three cycles. Results  Twenty-seven patients were enrolled (19 with relapsed and 8 with refractory; 10 with an IPI score of 3–5). The overall response rate was 63% [95% confidence interval (95% CI) 45–81%], including eight complete remissions (CR) and one unconfirmed CR (33%). The median duration of response was 9.9 months (95% CI 5.7–14.2 months). After a median follow-up of 18.6 months, the median progression-free and overall survival was 5.3 months (95% CI 3.9–6.7 months) and 15.1 months (95% CI 9.4–20.9 months), respectively, with a 1-year survival rate of 61.5%. Most common grade 3/4 hematologic toxicities were neutropenia (56%) and thrombocytopenia (35%), whereas no patient experienced grade 3/4 renal or neurotoxicity. Conclusion  The efficacy and toxicity profiles suggested that the ESHAOx can be an alternative option for patients with refractory/relapsed aggressive NHL. S. J. Sym and D. H. Lee contributed equally to this study.     

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;)     

Long-term outcome of mesna,ifosfamide, mitoxantrone,etoposide (MINE) regimen as a consolidation in patients with aggressive non-Hodgkin lymphoma responding to CHOP

In aggressive non-Hodgkin lymphoma (NHL), CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) regimen has been standard for decades, and rituximab has increased response rates and survival in CD20 positive patients, recently. The aim of this prospective trial was to evaluate the long-term efficacy and toxicity of MINE as a consolidation treatment in aggressive NHL patients who had achieved CR or unproven CR after six cycles of CHOP in the first line setting. The primary end-point was disease-free-survival (DFS). Thirty-eight patients were enrolled between February 1992 and May 2000. All of the patients received two cycles of MINE (mesna 1.3 g/m², ifosfamide 1.3 g/m², etoposide 65 mg/m² on days 1–3, and mitoxantrone 12 mg/m² on day 1, every 3 weeks) following response to CHOP. Initial bulky disease sites were also applied radiotherapy. Male/female ratio was 1.53(23/15). Median age was 49(30–73). Most of the patients had advanced stage (84.2% for stage >3) and high IPI score (79% for IPI score >2). Sixty percent had diffuse large cell histology. Median follow-up time was 118 months (9–195). Actual mean dose intensity was 88%. There were seven febrile neutropenia episodes. Two patients had grade two neuropathy, one had grade three mucositis and another one had non-neutropenic pneumonia. There was no early toxic death. No serious late toxicity was observed during long-term follow-up. Five- and 10-year DFS rates were both 65.3%. DFS rate in the patients with more than two poor prognostic factors according to IPI score is remarkably high (88%). Five- and 10-year OS was 62.5 and 59%, respectively. MINE regimen seems to be effective as a consolidation regimen, especially, in intermediate/high risk patients and has low early and late toxicities, and it warrants to be evaluated in phase III randomised trials with rituximab in CD20 positive aggressive NHL patients.     

A Multicenter,Open-Label,Noncomparative Screening Study of Enzastaurin in Adult Patients With Non-Hodgkin Lymphomas

PurposeTo assess the antitumor activity of enzastaurin in patients with non-Hodgkin lymphomas: T-cell lymphoma (n = 23): cutaneous and peripheral T-cell lymphoma; indolent B-cell lymphomas (n = 19): small lymphocytic, follicular grade 1 or 2, marginal zone lymphomas; and aggressive B-cell lymphomas (n = 15): follicular lymphomas grade 3, aggressive lymphoma with a clinical history. The primary objective was to determine overall tumor response. Secondary objectives included duration of response and safety.Materials and MethodsIn this multicenter, open-label, noncomparative, screening study conducted between December 2007 and February 2009, patients (≥ 18 years) who relapsed after ≥ 1 prior systemic treatment or who were intolerant to standard systemic therapy received 250 mg oral enzastaurin (125 mg tablets twice a day; a 1125-mg loading dose on day 1), in 28-day cycles for up to 2 years unless unacceptable toxicity or progressive disease occurred.ResultsResponses were seen in follicular lymphomas grade 3 (1/5, 20.0%), cutaneous T-cell lymphoma (2/11, 18.2%), small lymphocytic lymphomas (1/7, 14.3%), and aggressive lymphoma with a clinical history (1/10, 10.0%) in this heavily pretreated patient population (median prior therapies range from 4 to 10). Most drug-related toxicities were grade 1/2, the most common being diarrhea, peripheral edema, and pruritus.ConclusionsEnzastaurin was well tolerated but demonstrated modest responses across subgroups in this heavily pretreated patient population.     

A phase II study of topotecan in non-Hodgkin's lymphoma: an Ohio State University phase II research consortium study

Purpose: This multicenter phase II trial evaluated the efficacy and toxicity of the topoisomerase I inhibitor topotecan (TPT, 9-dimethylaminomethyl-10-hydroxycamptothecin) in patients with refractory or relapsing non-Hodgkin's lymphoma.

Patients and methods: Thirty-two patients with previously treated non-Hodgkin's lymphoma were accrued in this study from June 1992 to June 1997. Patients were eligible if they had measurable disease and had received two or less chemotherapy treatments for indolent lymphoma or no more than one treatment for aggressive lymphoma. Nineteen patients with aggressive lymphoma including seven with transformed indolent disease and 11 patients with indolent disease were treated. Two additional patients had both indolent and aggressive lymphoma in the bone marrow and lymph nodes at entrance into the study. Topotecan was administered as a 30-min infusion at a dose of 1.25 mg/m² for five days and repeated at three week intervals.

Results: Thirty-two patients were evaluable for toxicity and 29 patients were evaluable for response. There were five objective responses including two complete remissions and three partial remissions (17%; CI 4-30%). Four of the five responders had aggressive disease and had been responsive to prior chemotherapy. The duration of remissions were short, lasting a median of 2 months (range 2-52 months). The major toxicity seen was myelosuppression with 28 of the 32 patients having grade three or greater granulocytopenia.

Conclusion: Topotecan given as a five day 30 min infusion at a dose of 1.25 mg/m² has modest activity in previously treated non-Hodgkin's lymphoma as compared to other active agents.     

Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin's lymphoma.

PURPOSE: This single-center, dose-escalation study examines the safety, efficacy, and pharmacokinetics of epratuzumab (anti-CD22 humanized monoclonal antibody) in patients with recurrent indolent non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients had indolent NHL and recurrent disease after at least one chemotherapy regimen. Epratuzumab was administered intravenously at 120 to 1,000 mg/m2 over 30 to 60 minutes weekly for four treatments. RESULTS: Fifty-five patients received epratuzumab and were assessable for safety; 51 patients were assessable for response. Patients were heavily pretreated (50% had at least four prior regimens) and 49% had bulky disease (> or = 5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. More than 95% of infusions were completed in approximately 1 hour. Mean serum half-life was 23 days. Across all dose levels and histologies, nine patients (18%; 95% confidence interval, 8% to 31%) achieved objective response, including three complete responses (CRs). All responses were in patients with follicular NHL: 24% of these patients responded, including 43% in the 360 mg/m2 dose group and 27% in the 480 mg/m2 dose group. No responses were observed in other indolent histologies. Median duration of objective response was 79.3 weeks (range, 11.1 to 143.3 weeks), with median time to progression for responders of 86.6 weeks by Kaplan-Meier estimate. CONCLUSION: Epratuzumab was well tolerated at up to 1,000 mg/m2/wk (for 4 weeks) and had clinical activity. One third of responding patients achieved CR. A 43% objective response rate in follicular NHL patients treated at 360 mg/m2/wk indicates that this dose should be explored in additional studies.     

Clinical experience of bendamustine treatment for non-Hodgkin lymphoma and chronic lymphocytic leukemia in Spain

Bendamustine is a alkylating agent with a purine-like benzamidazole ring currently approved in Europe for indolent non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma. Our aim was to analyze retrospectively the efficacy and toxicity of bendamustine in NHL and CLL in Spain in the bendamustine Compassionate Use Program. Patients with relapsed/refractory NHL or CLL were eligible. Any regimen containing bendamustine was eligible. 109 patients were included from 22 institutions. Forty-nine patients had indolent NHL, 18 aggressive NHL and 42 CLL, being 44 patients (40%) refractory to previous treatment. 63% of patients had adverse events grade 3-4, mainly hematological. Overall response rate (ORR) was 66%, complete responses 30%. ORR observed in refractory patients was 45%. The median progression-free survival (PFS) was 13 months. Outcome was influenced by histology, number of previous treatments, resistance to previous chemotherapy and type of response achieved with bendamustine. Alone or in combination, bendamustine shows a meaningful clinical antitumor activity in patients with relapsed or refractory NHL or CLL, with an acceptable toxicity profile.     

MINE方案治疗复发或耐药的侵袭性淋巴瘤临床观察

背景与目的:复发或耐药侵袭性非霍奇金淋巴瘤(non-HodgkinQslymphoma,NHL)的治疗是当前恶性淋巴瘤治疗的难题,目前尚无标准的挽救性治疗方案。本研究目的是观察MINE方案(Mesna、IFO、Novantrone、VP-16)治疗复发或耐药侵袭性NHL的疗效和不良反应。方法:回顾性分析2001年1月至2003年6月收治的38例复发或耐药侵袭性NHL患者的临床资料,所有患者均接受过至少1个化疗方案的治疗,中位方案数为2个(1～4个),中位疗程数6个(2～12个)。采用MINE方案化疗2～6个疗程(中位疗程数4个)。结果:38例患者均可评价疗效和不良反应,总有效率47.4%,完全缓解率15.8%。B细胞来源淋巴瘤(26例)有效率57.7%,T细胞来源淋巴瘤(12例)有效率25.0%。全组1年生存率34.2%,2年生存率7.9%。主要不良反应为骨髓抑制,其中Ⅲ～Ⅳ度白细胞减少发生率为39.5%(15例),Ⅲ～Ⅳ度血小板减少发生率为13.2%(5例);1例患者出现Ⅲ度肝功能损害。结论:MINE方案为复发或耐药侵袭性NHL的经济、有效挽救治疗方案,不良反应可以耐受,但缓解时间较短,值得进一步研究应用。     

Non-Hodgkin's lymphoma in patients 70 years of age or older: factors associated with survival

The incidence of non-Hodgkin's lymphoma (NHL) has increased dramatically especially in persons over 60 years of age. We reviewed our experience in patients with NHL who were 70 years of age or older and seen between 1992 and 1998 in an effort to find any unique risk factors in this age group. There were 64 patients. Twenty-five had indolent disease and 38 had aggressive disease. The majority of patients with indolent lymphoma presented with nodal disease and were more likely to have bone marrow involvement. In contrast, 71% of patients with aggressive lymphoma presented with extra-nodal disease. Five of seven (71%) patients with indolent and 22 of 29 (76%) with aggressive NHL who received an Adriamycin containing regimen as first line therapy achieved a complete response. The International Prognostic Index (IPI) was a strong predictor of both survival (P<001) and response (P=007) for the group as a whole. The IPI accurately predicted the survival of patients with aggressive NHL (P=026). This was not the case with indolent lymphomas. This study suggests that elderly patients with NHL are more likely to have aggressive disease, a diffuse pathology and an extra-nodal presentation.     

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 .     

Phase II study of copanlisib,a PI3K inhibitor,in relapsed or refractory,indolent or aggressive lymphoma

BackgroundCopanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms.Patients and methodsThis phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis.ResultsThirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2–138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0–874) and 70 days (range 0–897), respectively; median duration of response was 390 days (range 0–825) and 166 days (range 0–786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression.ConclusionIntravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing.This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A).     

Phase II study of sequential topotecan and etoposide in patients with intermediate grade non-Hodgkin's lymphoma: a National Cancer Institute of Canada Clinical Trials Group study

Preliminary results indicate that inhibitors of the nuclear enzyme topoisomerase (topo) I, such as topotecan, may be active in non-Hodgkin's lymphoma (NHL). Pre-clinical studies have shown sequential administration of a topo I and II inhibitor has supra-additive anti-tumor effects in some model systems, and that greater cytotoxicity occurs if the topo I inhibitor is given first. We enrolled, 22 eligible patients with relapsed or refractory intermediate grade NHL in a phase II study ofsequential administration of topotecan 1.25 mg/m2 days 1-5 and etoposide 50 mg po b.i.d. days 6-12, every 28 days without G-CSF. Most patients had diffuse large B-cell lymphoma and all had received only one prior regimen (CHOP, 20 patients, or equivalent, 2 patients). Patients with stable or responding disease were allowed to proceed to high-dose therapy and autologous stem-cell transplant after 2 cycles of therapy. The 22 patients received a total of 62 cycles of topotecan + etoposide (median 2, range 1-6), and 4/22 completed all six planned cycles. Hematologic toxicity was significant and resulted in incomplete etoposide dosing in half of all cycles in 16/22 patients. Nineteen of twenty-two patients had grade 3/4 neutropenia, 12 had grade 3/4 thrombocytopenia, and 6 grade 3/4 anemia. Eleven patients had at least one episode of febrile neutropenia or had documented infection. Non-hematologic toxicity was mild. Four patients had a partial response (PR) (18.2%), nine had stable disease and seven progressed; three patients with stable disease went on to ABMT. The combination of topotecan and etoposide as given in this study has modest activity in relapsed/refractory aggressive histology NHL, and produces marked myelosuppression. Other doses and schedules combining topo I and II inhibitors, or topo I inhibitors with alkylating agents, should be explored with the addition of hematopoietic growth factors in this patient population.     

Activity of fludarabine in previously treated non-Hodgkin's low-grade lymphoma: results of an Eastern Cooperative Oncology Group study.

PURPOSE: Fludarabine (2-fluoro-arabanoside-monophosphate) is a new antimetabolite chemotherapeutic agent. We performed a multicenter, phase II study of this drug in previously treated patients with refractory or relapsed non-Hodgkin's lymphoma (NHL) to determine its response rate by histologic classification. PATIENTS AND METHODS: Sixty-two assessable patients were given 18 mg/m2 by intravenous (IV) bolus injection daily for 5 days, every 28 days. Forty-eight percent had previously had one chemotherapy regimen, and the remainder had had two regimens; 42% had had radiation. RESULTS: Patients received 273 cycles of fludarabine chemotherapy, with a median of two cycles and ranging up to 25 cycles. Sixty patients were assessable for response, including nine complete responses (CRs; 15%) and nine partial responses (PRs; 15%). The response rate for patients with lower-grade histology was 52% (13 of 25); the greatest response rate was seen in those with follicular small cleaved-cell lymphoma, including seven of 11 treated. Five responders remain in unmaintained remission; the median survival of responders is greater than 30 months. Toxicity included mild neutropenia and a 10% incidence of grade 3 neurologic toxicity with occasional reversible visual and auditory changes. CONCLUSION: Fludarabine is active in patients with previously treated NHL (particularly low-grade histologies). Future studies will examine its activity in combination with other chemotherapeutic agents in previously untreated patients.     

Subcutaneous interleukin-4 (IL-4) for relapsed and resistant non-Hodgkin lymphoma: a phase II trial in the North Central Cancer Treatment Group, NCCTG 91-78-51

Interleukin-4 (IL-4), a pleiotropic cytokine, has in vitro activity against non-Hodgkin lymphoma (NHL). This phase II study was conducted to learn the efficacy and toxicity of IL-4 in patients with NHL. Patients with relapsed or refractory indolent or aggressive NHL were eligible to receive 2.5 or 5.0 mcg/kg of subcutaneous IL-4 for 28 days of a 42-day cycle. Patients with response and acceptable toxicity after two cycles were eligible to continue treatment for six cycles. The target overall response rate (ORR) was 20%. Forty-one patients were enrolled and assessable for toxicity; two were ineligible after histology review. The ORR was 13% (5/39) with one complete and four partial responses. All responders were treated with 5.0 mcg/kg; the median time to progression was 84 days, the median duration of response for responders was 8.3 months. The most common toxicities of any grade in all patients were edema (66%), malaise (56%), and elevated liver function tests (56%). Grade 3 and 4 toxicities were more common at 5.0 mcg/kg, leading to a reduction in the starting dose. Although the study observed anti-tumor activity with IL-4, the ORR goal of the study was not achieved. Agents that target the IL-4 receptor can potentially benefit patients with NHL; however, alternative schedules using IL-4 in shorter duration and in combination with other agents would be required to overcome toxicities observed in this study.     

Pharmacokinetic profile and first preliminary clinical evaluation of bendamustine in Taiwanese patients with heavily pretreated indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Prior studies found bendamustine is efficacious in patients with indolent B‐cell non‐Hodgkin lymphoma (NHL). To date, no studies have reported the efficacy of bendamustine in a Chinese population. This multicentre phase II trial evaluated the pharmacokinetics (PK), safety and efficacy of bendamustine monotherapy in Chinese patients in Taiwan with pretreated indolent B‐cell NHL or mantle cell lymphoma (MCL). For PK assessments, patients were randomized (n = 16; 11 with indolent B‐cell NHL and five with MCL) to 90 or 120 mg/m² of bendamustine for the first cycle. Plasma levels of bendamustine and its two metabolites were analyzed. For efficacy and safety evaluations, bendamustine 120 mg/m² was given to all patients every 3 weeks starting at cycle 2 for a minimum of a total of six cycles. The median age of patients was 61.7 years, and the majority were men (75%). The median number of prior treatments was 4 (range, 1–9 regimens), and all patients were previously treated with rituximab. Bendamustine plasma concentration peaked near the end of infusion and was rapidly eliminated with a mean elimination half‐life (t_1/2) of 0.67–0.8 h. Of the evaluable patients (n = 14), the overall response rate was 78.6%, including 7.2% of patients having a complete response. Mean progression‐free survival was 27.5 weeks. The most common grade 3–4 adverse events were leucopenia (56.3%), neutropenia (56.3%) and thrombocytopenia (25%). In conclusion, bendamustine was efficacious and well tolerated in Taiwanese patients with indolent NHL and MCL with a similar PK profile to that of other populations. Copyright © 2014 John Wiley & Sons, Ltd.