氟达拉滨联合米托蒽醌、地塞米松治疗惰性淋巴瘤疗效分析

目的比较氟达拉滨（FLU）联合米托蒽醌（MIT）、地塞米松（DXM）（FMD方案）与CHOP方案治疗惰性淋巴瘤的疗效。方法73例初、复治惰性淋巴瘤病人分3组。A组：FMD初治组;B组：FMD复治组;C组：CHOP方案治疗组。结果A组的CR率为59．1％,高于B组的CR率28．6％（P〈0．05）,A组的总有效率（CR＋PR）86.4％,高于B组的总有效率（CR＋PR）57．1％（P〈0．05）。A组的CR率亦高于C组的CR率26．6％（P〈0．025）,A组总有效率高于C组的总有效率63.3％,但差异不显著（P〉0．05）。结论初治惰性淋巴瘤病人采用FMD方案疗效优于复治病人;初治惰性淋巴瘤病人采用FMD方案疗效优于CHOP方案。     

惰性淋巴瘤治疗进展

惰性淋巴瘤诊断时多为晚期,一般认为常规化疗不能治愈。随着新的化疗药物以及免疫靶向治疗抗CD20单克隆抗体利妥昔的广泛用于惰性淋巴瘤治疗,研究结果显示了利妥昔单药治疗复发/难治性惰性淋巴瘤的突出疗效;利妥昔单药或与化疗联合用于惰性淋巴瘤的一线诱导治疗以及维持治疗的显著效果,并可获得分子学缓解,使得惰性淋巴瘤的有效率和长期生存得到了明显改善。     

氟达拉滨联合方案治疗恶性淋巴瘤的临床疗效

背景与目的：氟达拉滨是抗病毒药阿糖腺苷的氟化核苷酸类似物，用于治疗慢性淋巴细胞性白血病和复发耐药的惰性淋巴瘤已显示了疗效。本研究的目的为评价氟达拉滨联合方案治疗恶性淋巴瘤的疗效和安全性。方法：2004年1月至2005年11月间本科收治经组织学确诊的接受含氟达拉滨联合化疗的恶性淋巴瘤患者共19例，其中惰性淋巴瘤患者11例，复发的进展性淋巴瘤患者8例。11例惰性淋巴瘤患者中，6例接受了FND（氟达拉滨25mg／m^2Ⅳ d1-3；米托葸醌10mg／m^2Ⅳ d1；地塞米松20mgPOd1～5，每4周重复）方案，5例接受了FC（氟达拉滨25mg／m^2Ⅳ d1-3；环磷酰胺300mg／m^2Ⅳ d1-3，每4周重复）方案。所有进展性淋巴瘤患者均接受了FND方案。结果：接受FND或FC化疗的惰性淋巴瘤患者，有效率91％，完全缓解（CR）率45．5％。进展性淋巴瘤息者中2例达部分缓解（PR），有效率25％。全组有效率63．1％。主要不良反应为骨髓抑制。FND组有69．5％周期发生Ⅲ／Ⅳ度中性粒细胞减少。FC组无Ⅳ度中性粒细胞减少，仅22．2％周期发生Ⅲ度中性粒细胞减少。发生肺部感染4例，外阴尖锐湿疣1例。其他不良反应均为轻度，以消化道反应为主。结论：含氟达拉滨的联合方案，对于惰性淋巴瘤患者具有肯定的疗效，不良反应可以耐受。     

氟达拉滨为主方案治疗复发难治性惰性非霍奇金淋巴瘤20例

目的 观察氟达拉滨为主方案治疗少见、复发、难治惰性非霍奇金淋巴瘤(NHL)的疗效及患者不良反应.方法 对20例少见、复发、难治性惰性NHL分别采用FMD(氟达拉滨+米托蒽醌+地塞米松)方案7例,FC(氟达拉滨联合环磷酰胺)方案8例和单用氟达拉滨5例,按照WHO疗效和不良反应评价标准进行临床评估.结果 20例患者中达完全缓解8例(40%),部分缓解9例(45%),有效率为85%.Ⅲ级以上不良反应:中性粒细胞减少共16例(80%),血小板减少共5例(25%),严重恶心、呕吐4例,轻度肝功能损害1例.结论氟达拉滨为主方案治疗少见、复发、难治性惰性NHL安全、疗效好、不良反应轻,氟达拉滨作为惰性NHL的一线治疗药物值得临床推广应用.     

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。     

CHOP与CNOP治疗非何杰金氏淋巴瘤的对比观察报告

ＣＨＯＰ（ＣＴＸ、ＡＤＭ、ＶＣＲ、ＰＤＮ）联合化疗方案是治疗非何杰金氏淋巴瘤（Ｎｏｎ—Ｈｏｄｇｋｉｎ′ｓＬｙｍｐｈｏｍａＮＨＬ）常用的、有效的方法之一。米托蒽醌是一有效的、广谱的、细胞周期非特异性抗癌药，化学结构与阿霉素相似，抗癌活性与ＡＤＭ相当或略高，它无氨基糖结构，心脏毒性较ＡＤＭ低。对确诊为ＮＨＬ３６例住院患者，随机分为ＣＨＯＰ组和ＣＮＯＰ组各１８例作临床对比观察。ＣＨＯＰ组ＣＲ２例、ＰＲ７例，有效率５０％（９／１８）；ＣＮＯＰ组ＣＲ４例、ＰＲ７例，有效率６１．１％（１１／１８），两组疗效相似（Ｐ＞０．０５）。     

氟达拉滨联合表柔比星治疗复发难治性惰性非霍奇金淋巴瘤

目的:探讨FE（氟达拉滨联合表柔比星）方案作为二线解救方案治疗复发难治性的惰性淋巴瘤（Non-Hodgkin's Lymphoma ,NHL ）的有效性和安全性。方法:经组织病理学证实的复发难治性惰性NHL 79例,按信封法随机分为FE方案组与FMD方案组。39例采用FE方案化疗（氟达拉滨25mg/m2/d ,d1～d3;表柔比星（EPI）60mg/m2/d ,d1,28天为1 周期）,40例采用FMD方案化疗（氟达拉滨25mg/m2/d ,d1～d3;米托蒽醌10mg/m2/d ,d1;地塞米松20mg/d ,d1～d5,28d 为1 周期）。 所有患者均至少完成2 个周期化疗。结果:FE组有效率（CR+PR）64.1% ,临床受益率（CR+PR+SD ）79.5% ,中位无进展生存期21个月,2 年总生存率71.8% ;FMD组有效率（CR+PR）57.5% ,临床受益率（CR+PR+SD ）75% ,中位无进展生存期20个月,2 年总生存率60% 。FE组的疗效略优于FMD组,但两组间差异无统计学意义（P>0.05）。 中位无进展生存期和2 年总生存率两组间亦无统计学意义（P>0.05）。 两组不良反应均以中性粒细胞减少和感染最为常见,其中Ⅲ～Ⅳ度骨髓抑制FE组15.4%（6/39）,FMD组29%（15/40）,经升血治疗处理恢复;肺感染FE组5.1%（2/39）,FMD组22.5%（9/40）。 FE组Ⅲ～Ⅳ度中性粒细胞缺乏和肺感染发生率均较FMD组轻,两组不良反应发生率间有统计学差异（P<0.05）。 结论:FE方案治疗复发难治性惰性NHL 的疗效肯定,骨髓毒性和肺感染发生率明显低于FMD组,是复发难治性惰性NHL 患者安全有效的解救方案,值得进一步推广应用。      

氟达拉滨联合方案治疗复发难治非霍奇金淋巴瘤临床疗效观察

目的观察氟达拉滨联合化疗治疗复发难治非霍奇金淋巴瘤临床疗效及安全性。方法38例复发难治非霍奇金淋巴瘤患者均采用FND方案：氟达拉滨30mg/m² d1~3,米托蒽醌10mg/m² d1,曲安西龙80mg pod 1~5, 28天一周期。结果全组患者CR 8例（21%）,PR 13例（34%）,有效率56%;其中20例复发难治惰性淋巴瘤患者CR7例（35%）,PR9例（45%）,有效率80%; 18例复发难治侵袭性淋巴瘤患者CR 1例（6%）,PR 4例（22%）,有效率28%（ χ²=10.45, P =0.001）。全组患者中位随访22（1~47）月,复发难治惰性淋巴瘤患者中位生存期45（2~47）月,中位无进展生存期18（2~34）月;复发难治侵袭性淋巴瘤患者中位生存期15（2~45）月,中位无进展生存期3（1~22）月。不良反应主要为骨髓抑制和肺感染。结论氟达拉滨联合方案治疗惰性淋巴瘤疗效肯定,对复发难治侵袭性淋巴瘤患者疗效尚可,不失为一种治疗选择。     

惰性淋巴瘤临床治疗的最新进展

由于惰性淋巴瘤自然病程相对较长、对化疗不够敏感,因此,如何选择恰当的治疗方案一直是肿瘤界关注的课题.目前临床有很多治疗方法可供选择,2000年ASH会议从常规化疗、抗CD20单克隆抗体治疗、骨髓及外周血干细胞移植3个方面介绍了惰性淋巴瘤治疗的最新进展.     

Long-term follow-up of a randomized trial of fludarabine-mitoxantrone, compared with cyclophosphamide, doxorubicin, vindesine, prednisone (CHVP), as first-line treatment of elderly patients with advanced, low-grade non-Hodgkin's lymphoma before the era of monoclonal antibodies.

BACKGROUND: This randomized study compared the efficacy and safety of fludarabine-mitoxantrone (FM) with mini-CHVP (cyclophosphamide, doxorubicin, vindesine, prednisone) in elderly patients with advanced, low-grade non-Hodgkin's lymphoma. PATIENTS AND METHODS: End points were remission rates [overall response (OR) and complete response (CR)], failure-free survival (FFS), survival and toxicity. One hundred and fifty-five patients were randomized, 144 were evaluable for safety and 142 for response. Each treatment arm was given as six monthly cycles, followed by three bimonthly cycles. FM comprised fludarabine (20 mg/m(2) i.v.), days 1-5, plus mitoxantrone (10 mg/m(2) i.v.), day 1. CHVP cycles comprised cyclophosphamide (750 mg/m(2) i.v. infusion), doxorubicin (25 mg/m(2) i.v.) and vindesine (3 mg/m(2) i.v.) on day 1, and prednisone (50 mg/m(2)) on days 1-5. RESULTS: FM therapy resulted in superior remission rates (OR 81% versus 64%, CR 49% versus 17%; P = 0.0004). Median FFS for FM patients was 36 months, compared with 19 months for CHVP patients, and has not yet been reached for early CR patients at 53 months. Treatment arm was the major risk factor influencing survival. Both treatments were well tolerated, with only few infectious complications. CONCLUSION: FM was more effective than CHVP in achieving OR and CR, and favorably affected the outcome.     

Fludarabine–Mitoxantrone–Rituximab regimen in untreated indolent non‐follicular non‐Hodgkin's lymphoma: experience on 143 patients

Indolent non‐follicular lymphomas (inFLs) are generally regarded as incurable, apart from extranodal mucosa‐associated lymphatic tissue lymphomas, which can be partially cured by surgery, local radiotherapy, or antibiotic treatment. The aim of the present study was to test the degree of effectiveness and the safety of the regimen containing fludarabine, mitoxantrone, and rituximab (FMR) in inFL patients considering all the different entities belonging to this group. An observational retrospective study was conducted on 143 inFL patients providing that their first chemoimmunotherapy performed was FMR regimen and diagnosis from September 2000 to March 2011. There were 32 small lymphocytic lymphomas and 111 marginal zone lymphomas. At the end of treatment, overall response rate was 96.5% with 88% of complete responses (CR) and 8.5% of partial responses. With a median follow‐up of 48 months, 10 out of 125 (8%) CR patients had disease relapse, yielding an estimated 9‐year disease‐free survival (DFS) of 74.9% and an estimated 10‐year overall survival of 92.8%. The estimated 9‐year progression free survival was 70.5%. The 10 relapsed patients showed lymphoma recurrence within 52 months: after this time, the DFS curve presented a plateau configuration. Only two (1.4%) patients developed a secondary hematological neoplasia. This study showed promising findings for the use of a fludarabine‐based regimen in combination with rituximab in the front‐line treatment of symptomatic inFL with a noteworthy high percentage of CR associated to an interesting long‐term DFS and favorable acute and long‐term safety profile. Copyright © 2014 John Wiley & Sons, Ltd.     

Low-grade non-Hodgkin's lymphoma - development of a new effective combination regimen (fludarabine,mitoxantrone and dexamethasone; FND)

Low-grade lymphoma is the commonest form of lymphoma in the USA and Europe with a long natural history with multiple responses and relapses. The tendency has been to use simple oral medication until patients have more advanced aggressive disease but new agents such as the purine analogues, mitoxantrone and monoclonal antibodies has led to re-evaluation of this approach. As purine analogues inhibit DNA repair in lymphoid cells, a new combination of fludarabine, mitoxantrone, and dexamethasone (FND) has been developed that is well tolerated and very effective. In a phase II study, in 51 patients 47% complete remissions and 47% partial remissions were noted. FND is now being used in a randomization comparative trial with alternating triple therapy as frontline treatment for low-grade lymphoma at the M. D. Anderson Cancer Center with monitoring by polymerase chain reaction for rearrangement of the bcl-2 gene in blood and bone marrow cells. The high activity and low morbidity of FND makes it as attractive as initial therapy for patients.     

Phase I and pharmacokinetic study of oral fludarabine phosphate in relapsed indolent B-cell non-Hodgkin's lymphoma.

BACKGROUND: The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of oral fludarabine phosphate in relapsed patients with indolent B-cell non-Hodgkin's lymphoma (B-NHL). PATIENTS AND METHODS: Patients received fludarabine phosphate orally for 5 days, for a total of one to three cycles. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria. Efficacy was assessed using the International Workshop Criteria for NHL. Pharmacokinetic samples were taken on day 1 and day 5 of the first treatment cycle. RESULTS: Twelve patients were enrolled. One patient at 40 mg/m2/day developed grade 4 hyperuricemia. At 50 mg/m2/day, one patient developed grade 3 febrile neutropenia and grade 4 leukopenia, and another patient showed lasting grade 4 neutropenia. Most common toxicities included grade 3 or 4 lymphopenia (83%), leukopenia (50%) and neutropenia (50%). All the toxicities were reversible. The overall response rate was 67%. The AUC0-24h values on day 5 indicated a dose-dependent increase in systemically available 2-fluoro-arabinofuranosyl-adenine (2F-ara-A). CONCLUSIONS: Oral fludarabine phosphate is safe and effective for relapsed patients with indolent B-NHL. The dose of 40 mg/m2/day is recommended for a following pivotal phase II study.     

Fludarabine-mitoxantrone combination-containing regimen in recurrent low-grade non-Hodgkin's lymphoma

Background: The promising results of fludarabine (FLU) in chroniclymphocytic leukemia have prompted its extensive evaluation in low-gradenon-Hodgkin's lymphoma (LG-NHL). Its different mechanisms of action make FLUan attractive partner for combination with other cytostatic agents.Patients and methods: We used a three-drug combination of FLU (25mg/m² i.v. on days one to three), mitoxantrone (10mg/m² i.v. on day one) and prednisone (40 mg per os on daysone to five) (FMP) to treat 48 patients with recurrent LG-NHL.Results: Of the 48 patients, 17 (35%) achieved complete responses(CR), 23 (48%) partial responses, while the remaining 8 (17%)showed no benefit from the treatment. The risk of lower CR rate wassignificantly correlated with the presence of advanced stage (IV) (P = 0.01),the number of previous regimens (>3) (P = 0.006), and the follicularhistologic subtype (P = 0.02). The major toxic effects observed wereneutropenia and infections; there was only one fatality, due to drug-relatedside effects.Conclusions: These data confirm the significant efficacy of the FMPfludarabine-mitoxantrone combination regimen in obtaining a good remissionrate with moderate toxicity in a particular subset of recurrent LG-NHL.     

Mitoxantrone-cyclophosphamide-rituximab: an effective and safe combination for indolent NHL

Treatment for extensive indolent lymphoma should combine optimization of efficacy without excessive toxicity. Rituxan may be an ideal agent for combinations with chemotherapy because of its non-cross-resistant toxicity profile and the potential for synergism. We present the results of 32 patients with indolent B-cell NHL who received a novel three-drug combination designed with the intent of preservation of both efficacy and quality of life. Patient characteristics were as follows, median age, 58 years (36-75 years); histology, follicular 16, SLL/CLL five, lymphoplasmacytic six, marginal cell five; relapsed or refractory, 10; untreated, 22. Patients first received cyclophosphamide 800 mg/m(2) and mitoxantrone 8 mg/m(2), iv on the same day, every 3 weeks for two cycles. Subsequently, patients received rituximab followed by mitoxantrone 8 mg/m(2) every 2 weeks for four cycles. The regimen, and particularly rituximab, was extremely well tolerated. Grade I/II, infusion-related toxicity was noted in 10%. Six patients achieved a PR and 23 a CR for an overall response of 90% (95% CI: 79-100%). The actuarial median TTP for all patients was 30 months. Molecular remissions were noted in 8/14 patients tested in CR. We conclude that the cyclophosphamide-mitoxantrone-rituxan (CyMiR) regimen is effective and extremely well tolerated. Furthermore, rituximab infusion-related morbidity is nearly completely eliminated.     

Proposed rituximab biosimilar BCD-020 versus reference rituximab for treatment of patients with indolent non-Hodgkin lymphomas: An international multicenter randomized trial

BCD-020 is a proposed rituximab biosimilar, which has shown high similarity to rituximab in quality and nonclinical studies in vitro and in vivo. International multicenter clinical trial was conducted to compare efficacy and safety of BCD-020 and reference rituximab in adult (older than 18 years) patients with indolent lymphomas (follicular lymphoma grade 1-2, splenic marginal zone lymphoma, and nodal marginal zone lymphoma). Pharmacokinetics, pharmacodynamics, and immunogenicity were also studied. Patients with no previous biologic treatment for lymphoma were randomly assigned 1:1 to receive BCD-020 or comparator 375 mg/m² for 4 weeks. Primary study outcome was day 50 overall response rate defined as complete or partial remission. Equivalence range was −20% to 20% for 95% CI for overall response rates difference. Secondary outcomes included adverse events, pharmacokinetics, pharmacodynamics, and immunogenicity. One hundred seventy-four patients were enrolled, 89 in BCD-020 arm and 85 in comparator arm. The overall response rate was 44.71% in BCD-020 arm and 41.89% in comparator arm. Limits of 95% confidence interval (CI) for difference of overall response rates between arms were (−12.62%-18.24%) showing equivalent efficacy. Sixty-one (68.54%) and 59 (69.41%) patients had at least one adverse event in BCD-020 arm or comparator arm, respectively. No unexpected adverse reactions were reported. Antidrug antibodies with no neutralizing activity were detected in two patients in comparator arm on day 14 further declining below detection threshold. Rituximab concentrations had equivalent pattern after intravenous administration of both drugs. Both drugs caused depletion of B-cells without significant influence on other blood cell lineages. In this study, we showed equivalent efficacy of BCD-020 and reference rituximab when used in patients with CD20-positive indolent lymphomas. We also confirmed pharmacokinetic equivalence of BCD-020 and reference rituximab. Safety profile, pharmacodynamics, and immunogenicity of BCD-020 were also comparable with those of reference rituximab.     

Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease

BACKGROUND:

The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced promising results in chronic lymphocytic leukemia and other lymphoproliferative disorders. The authors report the final results from a multicenter, prospective study examining FCR in Waldenstrom macroglobulinemia (WM).

METHODS:

Forty‐three patients with symptomatic WM that was untreated or pretreated with 1 line of chemotherapy received rituximab 375 mg/m² intravenously on day 1 and fludarabine 25 mg/m² and cyclophosphamide 250 mg/m² intravenously on days 2 through 4. FCR was repeated every 28 days for up to 6 courses.

RESULTS:

The overall response rate was 79%, and the major response rate of 74.4%, including 11.6% complete remissions (CRs) and 20.9% very good partial remissions. An amelioration of the quality of responses was observed during follow‐up, leading to 18.6% of CRs. No differences in terms of responses were observed among previously treated or untreated patients. Among the clinical and laboratory features that were considered, only the β2‐microglobulin level had a significant impact in terms of achieving a major response. The major toxicity reported was grade 3/4 neutropenia, which occurred in 45% of courses and was the main reason for treatment discontinuation. After the end of treatment, 19 patients (44%) had long‐lasting episodes of neutropenia. Three patients developed myelodysplastic syndrome during follow‐up.

CONCLUSIONS:

The FCR regimen was capable of neutralizing adverse prognostic factors and proved to be active in patients with WM, leading to rapid disease control and good‐quality responses. Because myelosuppression was the main concern, further studies are warranted to optimize dosages and treatment duration. Cancer 2011;. © 2011 American Cancer Society.     

Infectious disease associations in advanced stage, indolent lymphoma (follicular and nonfollicular): developing a lymphoma prevention strategy.

BACKGROUND: Eradication of Helicobacter pylori in gastric mucosa-associated lymphoid tumor can result in lymphoma remission. We prospectively identified/treated infections in nonbulky, advanced stage indolent lymphoma (follicular; nonfollicular lymphoma) eligible for observation. Materials and methods: Stool H. pylori, hepatitis C and Borrelia serologies, Borrelia and Chlamydia fixed tissue PCR, Chlamydia peripheral blood mononuclear cell PCR and hydrogen breath test for small bowel bacterial overgrowth (SBBO) were obtained. RESULTS: Fifty-six patients were enrolled. Positive infections: H. pylori (13); hepatitis C (3); SBBO (11). Negative: Borrelia (13); Chlamydophila psittaci (12, except one PCR). Lymphoma responses to antimicrobial therapy: H. pylori [one complete response (CR), 24+ months; one transient near CR]; hepatitis C [two CRs, 18+ and 30+ months; one partial response (PR) but hepatitis C virus persistent]; SBBO (one PR, 30+ months). Patients with associated infections, but without lymphoma CR, have required lymphoma treatment sooner than those without initial infections (treatment-free survival at 23.4 months median follow-up, 40.5% versus 74.7%, P = 0.01), indicating a different biology. CONCLUSION: Infections are common in advanced stage indolent lymphoma (37.5% in our series). Anecdotal lymphoma responses have been seen and three have been durable CRs (18 to 30+ months) with infection eradication alone. The identification and treatment of associated infections may be a first step towards developing a lymphoma prevention strategy.