苯达莫司汀/利妥昔单抗联合治疗可取代应用利妥昔单抗的标准化疗方案，用于晚期淋巴瘤的一线治疗。

一项纳入513例患晚期滤泡性、套细胞、边缘区、Waldenströms和小淋巴细胞性淋巴瘤的患者的III期试验显示，苯达莫司汀/利妥昔单抗联合治疗在无进展生存率方面的疗效优于利妥昔单抗/CHOP联合化疗，并且其毒性小于后者。
 
Mathias J. Rummel博士在美国血液学会(American Society of Hematology)年会的新闻发布会上表示，“苯达莫司汀有可能成为这些病种的一线治疗药物。”
 
盐酸苯达莫司汀是一种相对不知名的药物，在德国的部分地区已应用多年，并于2008年获准在美国上市。
 
在该研究中，苯达莫司汀/利妥昔单抗联合治疗的总缓解率与利妥昔单抗/CHOP联合治疗相似，分别为92.7%和91.3%。
 
然而，苯达莫司汀组的完全缓解率明显更高(39.6% 对 30%，P=0.0262)，这使得苯达莫司汀组的中位无进展生存期较CHOP组显著增加了20个月(54.9个月对 34.8个月，P =0.00012，危险比=0.57)。
 
德国吉森大学医院血液科主任Rummel博士表示，中位随访34个月时的总生存率无显著差异，但这在惰性疾病的治疗中是可以预期的。
 
苯达莫司汀组中3/4级血液学毒性反应的发生率显著低于CHOP组。这些毒性反应包括白细胞增多(1,450个周期中的12%对1,408个周期中的38%)和中性粒细胞减少(10.7%对46.5%)。两组中分别有4%和20%的患者需接受粒细胞集落刺激因子(G-CSF) 治疗。
 
Rummel 博士报告，苯达莫司汀组中各级感觉异常、口腔炎和感染性并发症(包括脓毒症)的发生率显著低于CHOP组，尽管苯达莫司汀组中荨麻疹和皮疹的发生率显著高于CHOP组。
 
他表示，毒性反应的减少可能与该研究中所用的苯达莫司汀剂量(90 mg/m2，连续2天，每4周)相关。该剂量低于美国批准的剂量(120 mg/m2，每3周)。
 
他说：“在与利妥昔单抗联用时，仅有一种单剂量可被推荐，即90 mg/m2 (每4周)，否则苯达莫司汀在毒性反应方面所具有的巨大优势就会丧失。需指出的是，这种剂量不是药品标签上标示的用量。并且，我深信……单纯通过增加苯达莫司汀的剂量，并不能提高疗效。”
 
波士顿Tufts医学中心癌症中心的 Richard Van Etten博士主持了这场新闻发布会。他表示，他对该研究结果持谨慎态度，并希望看到来自其他研究的证实数据。
 
他在接受采访时说：“抛开我对Rummel博士所说的话，我确实认为这尤其会改变治疗实践。但最好能够对其加以证实。他提出的关于苯达莫司汀剂量的观点完全正确。我听到很多、很多的人抱怨120 mg/m2的剂量过高。”
 
Rummel博士说，目前要重复该研究是不可能的，因为其不受此后维持治疗的影响，而多数患者目前接受利妥昔单抗进行维持治疗，并且所需随访时间将更长。
 
两位医生都不敢担保说，苯达莫司汀的治疗费用将会比CHOP低；尽管Rummel博士表示，较低的白细胞减少症发生率及G-CSF支持治疗可使这成为可能。

Indication(s):

Chronic lymphocytic leukemia (CLL).

Pharmacology:

Bendamustine is a bi-functional mechlorethamine derivative.Mechlorethamine and its derivatives dissociate into electrophilic alkyl groups.These groups form covalent bonds with electron-rich nucleophilic moieties.The bifunctional covalent linkage can lead to cell death via several pathways.The exact mechanism of action of bendamustine remains unknown.Bendamustine is active against both quiescent and dividing cells.

Clinical Trials:

The safety and efficacy of bendamustine were evaluated in an open-label, randomized, controlled multicenter trial comparing bendamustine to chlorambucil. The trial was conducted in 301 previously-untreated patients with Binet Stage B or C (Rai Stages I-IV) CLL requiring treatment. Patients were randomized to receive either bendamustine 100mg/m2 IV on Days 1 and 2 or chlorambucil 0.8mg/kg orally on Days 1 and 15 of each 28-day cycle. Efficacy endpoints of objective response rate and progression-free survival were calculated using a pre-specified algorithm based on NCI working group criteria for CLL. The results of this study demonstrated a significantly higher rate of overall response (59% vs. 26%) and a significantly longer progression-free survival (18 months vs 6 months) for bendamustine compared to chlorambucil.

Legal Classification:

Rx

Adults:

Give by IV infusion over 30 minutes.100mg/m² on Days 1 and 2 of a 28-day cycle, up to 6 cycles.May give allopurinol prophylactically for those at high risk of tumor lysis syndrome.Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥Grade 2 non-hematologic toxicity.Hematologic toxicity (≥Grade 3): reduce dose to 50mg/m² on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 25mg/m² on Days 1 and 2.Non-hematologic toxicity (clinically significant ≥Grade 3): reduce dose to 50mg/m² on Days 1 and 2 of each cycle. Subsequent cycles: may consider dose re-escalation.Severe renal impairment (CrCl <40mL/min) or moderate to severe hepatic impairment: not recommended.

Children:

Not recommended.

Warnings/Precautions:

Myelosuppression; monitor leukocytes, platelets, hemoglobin, neutrophils closely; restart treatment based on ANC and platelet count recovery. Renal or hepatic impairment. Monitor for infection, infusion reactions, tumor lysis syndrome. Pregnancy (Cat.D); avoid use.Nursing mothers: not recommended.

Interaction(s):

May be potentiated or antagonized by CYP1A2 inhibitors, inducers.

Adverse Reaction(s):

Neutropenia, pyrexia, thrombocytopenia, nausea, anemia, leukopenia, vomiting, asthenia, fatigue, malaise, dry mouth, somnolence, cough, constipation, headache, mucosal inflammation, stomatitis, increased bilirubin, increased AST or ALT; infection, infusion reactions (discontinue if severe), tumor lysis syndrome, skin reactions (if severe or progressive, withhold dose or discontinue).

How Supplied:

Single-use vial—1