Myelosuppression:

• Treatment with SPRYCEL^® (dasatinib) is associated with severe CTC Grade 3/4 thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in advanced-phase CML or Ph+ ALL than in chronic-phase CML. Myelosuppression was reported in patients with normal baseline laboratory values, as well as in patients with pre-existing laboratory abnormalities
  • Complete blood counts (CBCs) should be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated
  • In clinical studies, myelosuppression was managed by dose interruption, dose reduction, or discontinuation of study therapy
  • Hematopoietic growth factor has been used in patients with persistent myelosuppression

• Dasatinib caused platelet dysfunction in vitro and thrombocytopenia in humans. Severe CNS hemorrhage, including fatalities, occurred in <1% of patients
• Severe GI hemorrhage occurred in 4% of patients and generally required treatment interruptions and transfusions
• Other cases of severe hemorrhage occurred in 2% of patients
• Most bleeding events were associated with severe thrombocytopenia
  • Caution is advised in patients required to take medications that inhibit platelet function or anticoagulants

• Fluid retention was severe in 8% of patients, including pleural and pericardial effusions reported in 5% and 1%, respectively. Severe ascites and generalized edema were reported in <1% of patients. Severe pulmonary edema was reported in 1% of patients
  • Patients who develop symptoms suggestive of pleural effusion (dyspnea or dry cough) should be evaluated by chest X-ray
  • Severe pleural effusion may require oxygen therapy and thoracentesis
  • Fluid retention was typically managed by supportive care measures that included diuretics or short courses of steroids
  • Patients over the age of 65 years are more likely to experience fluid retention events, and should be monitored closely

• In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval)
• Nine patients had QTc prolongation as an adverse event. Three patients (<1%) experienced a QTcF >500 msec
• SPRYCEL should be administered with caution to patients who have or may develop prolongation of QTc, including patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome and patients taking anti-arrhythmic drugs, other medicinal products that lead to QT prolongation, or cumulative high-dose anthracycline therapy
  • Hypokalemia or hypomagnesemia should be corrected prior to SPRYCEL administration

• Drugs that may increase dasatinib concentrations are:
  • Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole)
  • Concomitant use of dasatinib and drugs that inhibit CYP3A4 should be avoided
  • If systemic administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction or temporary discontinuation should be considered
  • Grapefruit juice may also increase plasma concentrations of dasatinib and should be avoided
• Drugs that may decrease dasatinib concentrations are:
  • Strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital), which should be avoided. If SPRYCEL must be administered with a CYP3A4 inducer, alternative agents with less enzyme induction potential should be used or a dose increase of SPRYCEL should be considered
  • St John's Wort may decrease dasatinib plasma concentrations unpredictably and should be avoided

• Drugs that may have their plasma concentration altered by dasatinib are:
  • CYP3A4 substrates such as simvastatin. Therefore, CYP3A4 substrates with a narrow therapeutic index (e.g., alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids [ergotamine, dihydroergotamine]) should be administered with caution in patients receiving SPRYCEL

• The use of antacids should be considered
  • Simultaneous administration of SPRYCEL and antacids should be avoided
  • If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL

• The most frequently reported adverse reactions (reported in >20% of patients) included fluid retention events (37%), diarrhea (31%), headache (24%), skin rash (22%), nausea (22%), hemorrhage (21%), fatigue (21%), and dyspnea (20%)
• The most frequently reported serious adverse reactions included pleural effusion (9%), febrile neutropenia (4%), gastrointestinal bleeding (4%), pyrexia (3%), pneumonia (3%), dyspnea (3%), infection (2%), diarrhea (2%), congestive heart failure (2%), sepsis (1%), and pericardial effusion (1%)
• Grade 3/4 laboratory abnormalities in clinical studies in chronic phase CML included neutropenia (46%), thrombocytopenia (41%), anemia (18%), hypophosphatemia (10%), and hypocalcemia (2%)
• Grade 3/4 elevations of transaminase or bilirubin and Grade 3/4 hypocalcemia and hypophosphatemia were reported in patients with all phases of CML, but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML and Ph+ ALL
  • Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption
  • Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation

慢性髓细胞白血病治疗药物：Dasatinib

2006年6月，百时美施贵宝公司的酪氨酸受体激酶抑制剂dasatinib (Sprycel) 获得FDA批准，用于治疗对其他治疗耐药或不能耐受的成人慢性髓细胞白血病和费城染色体阳性的急性淋巴母细胞白血病。慢性髓细胞白血病一般分为3个阶段，慢性期、加速期和急变期，病程可持续几年，但到了急变期常常在半年内死亡。大多数CML病例会出现9 和22号染色体的部分互换，产生了一个截短的22号染色体，即费城染色体。融合的基因编码BCR–ABL蛋白,是CML的分子标记。BCR–ABL蛋白激酶抑制剂被认为可靶向治疗CML，Imatinib既是成功的例子。Imatinib已经成为CML的一线治疗药物，可以使大部分病人，特别是慢性期病人缓解，但每年仍有约4%的病人对Imatinib产生耐药，因此开发新的抑制剂仍是当务之急。

开发基础
对Imatinib耐药病人的基因研究发现，这些病人的BCR–ABL蛋白的激酶结构域发生了突变，干扰了Imatinib和激酶的结合。Imatinib只和ABL激酶的一种独一无二的非活性构形结合，这种构形特异性的结合方式是imatinib与ABL选择性结合的原因。ABL激酶结构域的突变会破坏这种构形的形成，造成imatinib无法与之结合。因此，假如某种抑制剂不是采用这种构形严格性的结合方式，那它对imatinib耐药突变的白血病细胞应该仍保留活性。Dasatinib是一种口服多激酶抑制剂，抑制的激酶包括BCR–ABL、SRC家族激酶、c-KIT和PDGFR- 。Dasatinib和ABL的结合对构形的要求并不严格，对imatinib耐药突变细胞仍有活性。Dasatinib对除T315I突变株的其他imatinib耐药突变细胞株都有活性。事实上，dasatinib可抑制来自于imatinib敏感或耐药病人体内BCR-ABL阳性骨髓前体细胞的增殖，延长imatinib耐药的白血病小鼠的生存时间。

临床试验
4项正在进行的单组临床试验考察了dasatinib的安全性和有效性，参加的病人是CML或费城染色体阳性的急性淋巴母细胞白血病病人，病人对imatinib 耐药或无法耐受。186名为CML慢性期病人，107名为CML加速期病人，74为髓系CML急变期病人，78名为淋巴系CML急变期病人。CML慢性期的首要有效性终点是主要细胞遗传学反应(MCyR)，定义为Ph+阳性细胞完全清除（完全细胞遗传学反应）或实质性减少（减少至少65%）。CML加速期和急变期以及急性淋巴母细胞白血病的首要有效性终点是主要血液学反应(MaHR)，定义为或者为完全血液学反应，或者无白血病迹象。dasatinib(70mg，口服，每日两次)的治疗使各期CML病人和急性淋巴母细胞白血病患者获得了细胞遗传学和血液学反应：慢性期CML 病人的McyR率为45%，完全反应率为33%。加速期病人的MaHR率为59%，髓系急变期病人的MaHR率为32%，淋巴系急变期病人的MaHR率为31%。Ph+急性淋巴母细胞白血病的MaHR率为42%。在CML慢性期、加速期和髓系急变期病人的6个月随访期内，血液学和细胞遗传学反应保持稳定。淋巴系急变期MaHR持续的中位时间为3.7个月，Ph+急性淋巴母细胞白血病人MaHR持续的中位时间为4.8个月。

适应症
Dasatinib被FDA批准用于治疗对之前治疗耐药或无法耐受的成人慢性期、加速期、髓系或淋巴系慢性髓性白血病。Dasatinib的有效性是以血液学和遗传学反应为基础，目前还没有对照试验来显示dasatinib的临床益处，例如疾病相关症状的改善或生存时间的延长。Dasatinib也被批准用来治疗对之前治疗耐药或不能耐受的Ph+急性淋巴母细胞白血病人。

新药开发现状

其他几种BCR–ABL酪氨酸激酶抑制剂正处于临床前或临床开发阶段，其中进展最迅速的是 nilotinib,是一种比imatinib活性更强的BCR–ABL抑制剂。 与dasatinib一样,其中的几种化合物也具有多重抑制活性，可抑制ABL和SRC激酶家族的多个成员。其中两个化合物SKI-606和INNO-406(NS-187)已进入I期临床试验阶段。 Imatinib, dasatinib和nilotinib对T315I突变细胞系都没有活性，但一种aurora激酶抑制剂MK 0457(VX 680)则对该突变细胞也有活性。其他T315I抑制剂还有AT9283、KW2449和homoharringtonine。但这些双重抑制剂的延长生存时间的临床益处还有待证实。CML的长期治疗可能需要激酶抑制剂、法尼酯转移酶抑制剂以及其他作用机制化合物的联合应用。可以控制和清除残余癌细胞的免疫疗法也是有价值的。