Combined thalidomide and cyclophosphamide treatment for refractory or relapsed multiple myeloma patients: a prospective phase II study

Thalidomide is an effective agent for patients with refractory multiple myeloma (MM) with a response rate of 30–40% at doses of 200–800 mg but with considerable side effects. We questioned whether lower doses of thalidomide in combination with a daily dose of cyclophosphamide might be an effective regimen with fewer side effects. We included 38 patients with relapsed or refractory MM. The median doses of thalidomide and cyclophosphamide were 100 and 95 mg/day, respectively. Side effects were observed in all patients, with neurotoxicity as the most troublesome. With a median follow-up of 14 months 84% of the patients responded, including 64% partial responses. The median time of progression-free survival was 30 months and the median overall survival time was 20 months. In conclusion, the results demonstrate that the combination of low-dose thalidomide with a daily dose of cyclophosphamide is an effective regimen with a high overall response rate and manageable side effects.This work is financially supported by research funding from the KWF (Dutch Cancer Society)Conflict of interest: There are no financial and personal relationsships with other people or organisations that could inappropriately influence (bias) our work.     

Phase II and pharmacokinetic study of thalidomide in Japanese patients with relapsed/refractory multiple myeloma

To obtain approval from the Ministry of Health, Labor and Welfare of Japan, a phase II study was conducted to assess the pharmacokinetics and pharmacodynamics of thalidomide along with its efficacy and safety in Japanese patients with multiple myeloma. Between 2005 and 2006, 42 patients were enrolled, and 37 patients met eligibility criteria. Of the 37 patients, 3 were excluded from efficacy analysis because of short duration of thalidomide administration (<4 weeks). The overall response rate was 35.3% (12/34), including partial response of 14.7% (5/34) and minimal response of 20.6% (7/34). The adverse events observed in high frequency (>40%) were leukopenia, neutropenia, drowsiness, dry mouth, and constipation. Grade 3 neutropenia was observed in nine cases. Peripheral neuropathy and eruption were observed in about one-quarter of the patients. Deep vein thrombosis was not observed. At a single oral dose of thalidomide (100 mg), the C _max was 1.68 ± 0.41 μg/ml, T _max was 4.54 ± 1.71 h, T _1/2 was 4.86 ± 0.44 h, and AUC was 15.87 ± 3.05 μg h/ml. Low-dose thalidomide was an effective and tolerable treatment for Japanese patients with relapsed/refractory myeloma. Leukopenia and neutropenia were the most serious adverse events. The pharmacokinetics was similar to those observed in Caucasian patients.     

沙立度胺治疗急性白血病近期临床疗效观察

目的 探讨沙立度胺(反应停)在治疗急性白血病(AL)中的作用。方法 38例AL中,初治27例,随机分为常规化疗加反应停治疗(A)组和常规化疗(B)组。复治11例,列为C组,全部应用化疗加反应停。用Ⅷ因子相关抗原和CD34单抗免疫组化染色的方法,观察患者治疗前后骨髓微血管密度(MVD)。用ELISA的方法测定患者治疗前后血清血管内皮细胞生长因子(VEGF)的浓度。反应停起始剂量200mg/d,每1周增加50mg/d,直到400-500mg／d,应用4-6个月。结果 两组初治病例的完全缓解(CR)率和有效率：CR 部分缓解(PR)及达CR所需疗程数用或不用反应停均无差异,其CR率和有效率分别为57．1％和53．8％及78．6％和76．9％。复治组CR率27．3％,有效率54．5％。A、B两组CR患者随访6个月,A组复发率较低。患者MVD、VEGF治疗前与正常对照组相比差异非常显著(P＜0．001)。治疗前VEGF水平与疗效呈负相关。用反应停组无特殊的不良反应。结论 反应停治疗可维持AL患者的持续缓解状态,减少复发。在AL的治疗中加用反应停是合理的新的治疗策略。     

低剂量反应停治疗原发性骨髓纤维化的临床研究

目的:探讨低剂量反应停治疗原发性骨髓纤维化的临床疗效。方法:原发性骨髓纤维化患者21例,反应停剂量为≤100mg/d,根据治疗前后外周血白细胞、血红蛋白、血小板、脾脏大小的变化及临床症状的改善来评定疗效,并观察骨髓病理检查及药物的不良反应。结果:21例患者中有18例完成了6个月的疗程,2/4患者白细胞从>15×109/L[(15.4~31.2)×109/L]降至<15×109/L;对于贫血的改善,CR2例(2/18,11.1%),PR5例(5/18,27.8%),MR4例(4/18,22.2%);6/10例患者血小板从<100×109/L[(30~90)×109/L]升至正常;18例脾大的患者中,有1例CR,2例PR,2例脾脏缩小≥25%,3例脾脏缩小<25%,有效率为44.4%。5例治疗有效者复查骨髓活检较治疗前无明显变化。反应停的不良反应主要表现为疲乏、便秘及淡漠。结论:反应停是一种安全、经济、有效的治疗原发性骨髓纤维化的新方法。     

Von Willebrand''s disease and angiodysplasia treated with thalidomide

A 54-year-old man with type IIB VWD and severe angiodysplasia had such a large blood loss from the bowel that it was difficult to keep up with transfusion requirements. Treatment with factor eight concentrate barely slowed the loss. D.D.A.V.P., Octreotide, and recombinant activated Factor VII, tried separately, were ineffective. The use of Thalidomide at a dose of 150 mg daily has rendered him free from blood loss for the last six months and we suggest would be worth a trial in similar cases.     

A phase II study of thalidomide and vinblastine for palliative patients with Hodgkin's lymphoma

INTRODUCTION: Patients with Hodgkin's Lymphoma (HL) who relapse or progress after primary therapy and subsequent high dose chemotherapy with autologous stem cell transplantation (ASCT) cannot be cured with conventional treatment. We combined thalidomide (THAL), an agent with anti-angiogenic and immunomodulatory properties, with vinblastine, which is active after ASCT, to determine the objective response rate, improvement in B symptoms and toxicity in patients with refractory HD. METHODS: Patients were eligible if they HD that progressed after chemotherapy and ASCT or had declined or were ineligible for curative therapy. Treatment consisted of THAL 200 mg orally given daily. After 2 weeks, VBL 6 mg IV was given weekly x 6 doses on an eight-week cycle. Response and toxicity assessment occurred following each cycle. RESULTS: Eleven patients were enrolled, 1 progressed within 6 days of study enrollment and was subsequently treated with alternative palliative therapy and thus 11 patients are response evaluable and 10 are evaluable for toxicity. Patient characteristics: relapsed after ASCT: 7; median number of prior chemotherapy regimens: 3 (range 1-5); median time to progression post-ASCT: 7 months (range 2-29). Four patients had a partial response to treatment (response rate 36%); two patients had stable disease. B symptoms were present at enrollment in four patients and resolved completely on treatment in two patients. Five had disease progression within 3 months of starting treatment. The median duration of response was 9 months (range 0-22 months). Toxicity was mild and limited to grade 2 neuropathy in 6 patients and grade 2 or 3 neutropenia in 4 patients. CONCLUSIONS: In this small study in chemotherapy- refractory HL, THAL and VBL demonstrated encouraging activity with some durable responses and acceptable toxicity. These results suggest that chronic low dose chemotherapy combined with less toxic immunomodulatory or anti-angiogenic drugs warrants further study.     

Diarrhoea in a patient with metastatic melanoma:Ipilimumab ileocolitis treated with infliximab

Administration of ipilimumab,a cytotoxic T-lymphocyte associated antigen-4-blocking monoclonal antibody,leads to enhancement of the anti-tumor T-cell respons and as a result shows a significant survival benefit in metastatic melanoma patients.Therefore patients are currently receiving this promising therapy as a secondline strategy.Unfortunately,by activation of the T-cell immune reponse,ipilimumab therapy may lead to an unwanted induction of different autoimmune phenomena.Diarrhoea and colitis occur in up to one third of patients.Here we present a case of ipilimumab induced ileocolitis which was successfully treated with infliximab,an anti-tumor necrosis factor monoclonal antibody,after corticosteroid therapy failure.Although formal trials are lacking,recently publicated series suggest that infusional therapy of infliximab is effective in ipilimumab induced ileocolitis.     

沙立度胺对多发性骨髓瘤患者细胞因子影响的临床研究

目的:探讨沙立度胺对多发性骨髓瘤(MM)患者几种细胞因子的免疫调节作用。方法:用ELISA方法检测沙立度胺治疗前后患者血清中干扰素-γ(IFN-γ)、白细胞介素(IL)-6、IL-10浓度的变化。结果:22例患者治疗前IFN-γ水平明显低于正常人(P<0.01),IL-6、IL-10水平明显高于正常人(均P<0.01);治疗后IFN-γ水平较治疗前无明显变化(P>0.05),12例治疗有效者的IL-6、IL-10水平较治疗前明显降低(P<0.01),10例治疗无效者的IL-6、IL-10水平较治疗前降低,但差异无统计学意义(P>0.05)。结论:通过降低MM患者血清中IL-6、IL-10水平可能是沙立度胺治疗MM有效的机制之一。     

沙立度胺治疗多发性骨髓瘤基因表达的改变

目的 应用抑制差减杂交法研究沙立度胺(反应停)对多发性骨髓瘤(MM)骨髓细胞基因表达的影响,探讨反应停治疗MM的分子机制。方法 随机选取1例初发MM患者,给予反应停治疗,治疗前后均留取骨髓,提取总RNA并分离mRNA,逆转录合成cDNA。分A、B组分别进行抑制差减杂交,所得的差减cDNA利用抑制PCR进行选择性扩增,并连接于T载体,转化JMl09感受态苗,构成差减cDNA文库,经蓝白斑筛选后挑选白色菌落,提取质粒,进行序列测定,将所得的每一个序列通过Email发往美国国立卫生研究院生物信息中心,进行同源性比较分析。结果 A组分离出8个下调基因片段包含7个已知基因：人核糖体蛋白L19,人IgGλ链可变区,含Alu重复组分,NADH—泛醌氧化还原酶链2,延长因子1-γ,人β珠球蛋白区,人40S核糖体蛋白S4。B组分离出的7个上调基因片段包含6个已知基因：细胞色素B,被1,25-二羟维生素D3上调基因(VDUPl),NADH-泛醌氧化还原酶20Kd亚单位,μ-需钙蛋白酶大亚单位,转录-调控肿瘤蛋白1(TPT1),外被体蛋白α亚单位。结论 反应停通过改变上述基因的表达,产生促进凋亡和抗血管生成作用。     

A phase II trial of cyclophosphamide,lenalidomide and dexamethasone in previously treated patients with AL amyloidosis

Immune-modulatory drugs are active in immunoglobulin light-chain amyloidosis and the addition of alkylating agents can potentiate their action. In this phase II prospective trial we used cyclophosphamide, lenalidomide and dexamethasone in the treatment of 21 patients who were refractory (n=13, 62%) or relapsed (n=8, 38%) after prior treatment including melphalan in all cases, bortezomib in 4 and thalidomide in 6. Median number of cycles administered was 4 (range 2–9 cycles). Severe adverse events were observed in 57% of patients, most common being neutropenia (29%). The hematologic response rate was 62%, with one complete response and 5 very good partial responses. Overall median survival was three years. The achievement of CR/VGPR was associated with a significant survival advantage. The combination of cyclophosphamide, lenalidomide and dexamethasone is an effective treatment for relapsed/refractory AL amyloidosis, and good quality hematologic response should be the aim of treatment in this setting.(clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00607581","term_id":"NCT00607581"}}NCT00607581)     

Phase II trial of the dopaminergic inhibitor pimozide in previously treated melanoma patients

Pimozide, a potent neuroleptic which inhibits the release of pituitary releasing factors and is an effective dopamine antagonist, was administered to 30 patients with previously treated metastatic melanoma. Six patients were inevaluable because of poor drug tolerance (two), disease progression within 1 week and death within 2 weeks (three), and death from other causes (one). Among the 24 evaluable patients, two had complete response, two had partial response, and two had disease stabilization. Responses were observed in soft tissue, lymph nodes, liver, and lung. Toxic effects consisted of extrapyramidal manifestations in nine patients and malaise in seven. Pimozide has activity in patients with previously treated metastatic melanoma (17% response rate in evaluable patients) and merits consideration of further study in combination regimens.     

Efficacy and safety of thalidomide in patients with hepatocellular carcinoma

INTRODUCTION Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer in the world. About one million people die of it each year[1,2]. Particularly in Taiwan, it poses a tremendous threat to citizens’ health and lives. HCC has been the leading c…     

Intermittent interferon and polychemotherapy in metastatic melanoma

This study was conducted to evaluate the efficacy and the tolerability of a four-drug chemotherapy regimen combined with interferon (IFN) in metastatic melanoma. Between March 1991 and August 1993, 55 patients with advanced melanoma were enrolled for the present multicentre phase II study. Fortynine patients were eligible and evaluable for toxicity; 48 patients were evaluable for response. The treatment schedule consisted of a 5-day regimen of dacarbazine, vincristine, bleomycin and lomustine, plus 6×10⁶ IU IFN three times weekly subcutaneously for 2 weeks starting on day 8. The cycle was repeated on day 29. Among the 48 assessable patients, 16 objective responses were seen, yielding a response rate of 33% (95% confidence interval 20%–46%). Seven patients achieved a complete response (CR) of a median of 6 + months (range 1 + to 21 + months) and 9 patients achieved a partial response (PR) of a median of 9 months (range 4–13 months). The median overall survival was 12 + months (range 6+ to 23 + months) for the patients with CR and 15 + months (range 8–20 months) for the patients with PR. Even the survival of the 7 patients with stable disease was fairly long (median 12, range 7–17 months), appearing to be significantly longer than the survival of the 25 patients with progressive disease (median 5, range 1–24 + months). The treatment was moderately well tolerated, although all patients experienced some mild form of toxicity, mostly gastrointestinal symptoms, neurotoxicity and haematotoxicity. Grade 3–4 adverse effects were noted in 39% of the patients. No toxic deaths occurred. It can be concluded that the present regimen produces meaningful responses for patients with metastatic melanoma. A randomised study is needed to determine the effect on survival.Abbreviations IFN interferon - DOBC dacarbazine, vincristine, bleomycin, lomustine     

环孢素A单独或联合沙利度胺治疗骨髓增生异常综合征

目的初步评价环孢素A单独应用或联合沙利度胺治疗骨髓增生异常综合征的疗效与不良反应。方法于2000年10月至2005年10月取中国医学科学院中国协和医科大学血液学研究所血液病医院血液六科的32例骨髓增生异常综合征患者,随机分为两组,分别接受了环孢素A(A组,n=14)或环孢素A联合沙利度胺(B组,n=18)治疗,比较两组的疗效和不良反应。结果共15例患者取得血液学进步[A组3例(21.4%),B组12例(66.7%),P<0.05]。A组红系显效3例;血小板显效2例,有效1例;中性粒细胞显效2例,有效1例。B组红系显效11例,有效1例;血小板显效5例,有效2例;中性粒细胞显效3例,有效3例。A组11例依赖输血的患者中2例(18.2%)脱离输血,B组14例依赖输血的患者中9例(64.3%)脱离输血,二者疗效比较差异有统计学意义(P<0.05)。共9例患者出现肝功能异常[A组3例(21.4%),B组6例(33.3%),P=0.457],3例出现肾功能异常[A组1例(7.1%),B组2例(11.1%),P=0.702],经停药或治疗后均好转。结论联合环孢素A和沙利度胺治疗骨髓增生异常综合征疗效较单用环孢素A好,出现肝肾功能异常是可逆性的。     

Phase II trial of ifosfamide with mesna in previously treated metastatic sarcoma

Ifosfamide given to 42 patients iv at 2-2.5 g/m2/day X 4 resulted in partial responses in ten of 28 (36%) evaluable patients with adult soft tissue sarcomas, including two of two with chondrosarcoma; none of nine with pediatric sarcomas (Ewing's sarcoma, osteogenic sarcoma, or rhabdomyosarcoma) achieved partial response. All of the pediatric patients had failed to respond to complicated three- to six-drug regimens of up to 18 months in duration. The response rates in patients with and without prior cyclophosphamide (32%; seven responses among 22 patients; and 20%, three responses among 15 patients) were not significantly different, supporting in vitro evidence of a lack of cross-resistance between the two related compounds. Myelosuppression was dose-limiting. Hemorrhagic cystitis was not observed in patients treated with 400-500 mg of mesna iv every 4 hours during ifosfamide treatment. Nausea and vomiting were generally mild or moderate. Alopecia was universal but reversible. Of the first 11 patients, five became somnolent or developed visual hallucinations (during six of the 12 total courses administered to the five patients). Only one patient had two episodes of neurotoxicity. After reduction of the use of iv antiemetics and major narcotics, single episodes of neurotoxicity were seen in five of the next 27 patients. An asymptomatic acidosis developed in most patients, requiring bicarbonate replacement in one. Ifosfamide appears to be active in previously treated patients with sarcomas and should be evaluated in patients with less extensive prior treatment.     

环孢素A单独或联合沙利度胺治疗骨髓增生异常综合征

目的初步评价环孢素A单独应用或联合沙利度胺治疗骨髓增生异常综合征的疗效与不良反应。方法于2000年10月至2005年10月取中国医学科学院中国协和医科大学血液学研究所血液病医院血液六科的32例骨髓增生异常综合征患者，随机分为两组，分别接受了环孢素A（A组，n=14）或环孢素A联合沙利度胺（B组，n=18）治疗，比较两组的疗效和不良反应。结果共15例患者取得血液学进步[A组3例（21．4％），B组12例（66．7％），P〈0．05]。A组红系显效3例；血小板显效2例，有效1例；中性粒细胞显效2例，有效1例。B组红系显效11例，有效1例；血小板显效5例，有效2例；中性粒细胞显效3例，有效3例。A组11例依赖输血的患者中2例（18．2％）脱离输血，B组14例依赖输血的患者中9例（64．3％）脱离输血，二者疗效比较差异有统计学意义（P〈0．05）。共9例患者出现肝功能异常[A组3例（21．4％），B组6例（33．3％），P=0．457]，3例出现肾功能异常[A组1例（7．1％），B组2例（11．1％），P=0．702]，经停药或治疗后均好转。结论联合环孢素A和沙利度胺治疗骨髓增生异常综合征疗效较单用环孢素A好，出现肝肾功能异常是可逆性的。