Non-hematologic Adverse Reactions Research Articles

Efficacy of nilotinib in the first-line treatment of chronic myeloid leukemia and the analysis of factors affecting molecular responses

目的探讨尼洛替尼一线治疗慢性髓性白血病（CML）的疗效及安全性，并分析影响实现主要分子学反应的因素。方法回顾性分析郑州大学附属肿瘤医院2014年1月至2017年6月收治的86例新诊断为CML的患者，均接受尼洛替尼300 mg每日两次作为一线治疗，其中男性49例，女性37例。结果12个月时获主要分子学反应（MMR）、分子学反应4（MR4）、分子学反应4.5（MR4.5）的患者比例分别为59.3%、22.1%、15.1%；24个月时，获MMR、MR4、MR4.5的患者比例分别为76.2%、44.0%、27.4%。中位随访42（21~66）个月，中位无进展生存（PFS）时间为42（9~66）个月，PFS率为93%。BCR-ABLIS融合基因较诊断时下降一半所需要的时间定义为减半时间（HT），HT是CML患者12个月能否达到MMR（OR=0.896，P<0.001）及MR4.5（OR=0.377，P=0.003）的影响因素。非血液学不良反应中最常见的为皮疹（37.2%）和头痛（32.6%），大多数为1/2级，血液学不良反应主要为中性粒细胞减少（27.9%）和血小板减少（32.4%）。结论尼洛替尼一线治疗CML具有较优的有效性和安全性，HT≤13.68 d可能是长期无进展生存的保护因素。

Toxicity profile of Doxorubicin-Cyclophosphamide and Doxorubicin-Cyclophosphamide followed by Paclitaxel regimen and its associated factors among women with breast cancer in Ethiopia: A prospective cohort study.

Management of patients with breast cancer undergoing chemotherapy is complicated by a very high rate of adverse drug reactions which is even more challenging in developing countries like Ethiopia where the toxicity profile of chemotherapy is lacking. The present study aimed at evaluating the toxicity profile of Doxorubicin-Cyclophosphamide (AC) and Doxorubicin-Cyclophosphamide→Paclitaxel (AC→T) regimens among 146 patients with breast cancer in Ethiopia. This prospective cohort study, with the median of six months' follow-up, was conducted from January 1 to September 30, 2017 GC at the only nationwide oncology center, Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia. Seventy-one patients received AC, while 75 received AC-T regimen. The toxicity with the highest grade during any cycle was considered as the toxicity grade for that patient. SPSS version 22 was used for analysis. The overall frequent non-hematological adverse drug reactions reported for both regimens were fatigue 144 (98.7%), dysgeusia 142 (97.3%), skin hyperpigmentation 141 (96.6%), nausea 136 (93.2%), vomiting 129 (88.4%), gastritis 122 (83.6%), peripheral neuropathy 108 (74%), and myalgia/arthralgia 110 (75.3%). Neutropenia 107 (73.3%), leukopenia 102 (69.9%), and anemia 51 (34.9%) were the most frequent overall grade hematological toxicities reported. However, those received AC regimen suffered more from grade 2 and above leukopenia (35.2% vs. 17.3%, P = 0.014), anemia (16.9% vs. 2.7%, P = 0.004), and alkaline phosphatase increment (11.3% vs. 2.7%, P = 0.039) than AC-T regimen. On the contrary, those received AC-T regimen suffered more from severe arthralgia/myalgia (2.8% vs. 2%, P = 0.001), peripheral neuropathy (1.4% vs. 36%, P = 0.000), and gastritis (14.1% vs. 29.3%, P = 0.026) than AC regimen. Pretreatment blood cell counts, having stage IV breast tumor, older age, and lower body surface area were significant predictors of grade 2 to above hematological toxicities. Older age, arthralgia/myalgia, and skin hyperpigmentation occurred during the cohort were significant predictors of grade 2 to above oral mucositis, peripheral neuropathy, and fatigue, respectively. Patients who received the AC regimen suffered more from hematological abnormalities, while those on the AC-T regimen experienced more of non-hematological toxicities. Overall, we report high incidences of AC and AC-T regimens-induced toxicities in Ethiopian women with breast cancer, and they may require prior support based on pretreatment blood counts, age and body surface area, and close follow-up during chemotherapy.

Safety and efficacy analysis of low-dose apatinib in treatment of advanced malignant tumors

Objective To investigate the safety and efficacy of low-dose apatinib in treatment of advanced malignant tumors. Methods The clinical data of 54 patients with advanced malignant tumors who were admitted to Shanxi Dayi Hospital from March 2015 to March 2018 were analyzed retrospectively. These patients were treated with apatinib at doses of 250 mg (29 cases) and 500 mg (25 cases) after initial treatment or failure of multi-line treatment. There were 15 cases of gastric cancer, 11 cases of lung cancer, 9 cases of ovarian cancer, 7 cases of liver cancer, 6 cases of soft tissue sarcoma, 3 cases of esophageal cancer, 2 cases of melanoma, and 1 case of peritoneal cancer. The objective response rate (ORR), disease control rate (DCR), progress free survival (PFS) and overall survival (OS) were analyzed, and the efficacy and related adverse reactions were evaluated. Results The adverse reactions of 54 patients could be evaluated. Non-hematological drug-related adverse reactions were most common with hypertension, hand-foot skin reaction and proteinuria, while hematologic drug-related adverse reactions were most common with leukopenia and thrombocytopenia. All patients were well tolerated. The incidence of drug-related adverse reactions in the 250 mg dose group was lower than that in the 500 mg dose group, and the incidence of grade Ⅰ-Ⅱ hypertension between the two groups was statistically different (χ 2=6.268, P=0.012). Short-term efficacy: ORR of the patients in the 250 mg and 500 mg dose groups was 6.9% (2/29) and 12.0% (3/25), respectively; DCR was 41.4% (12/29) and 52.0% (13/25), respectively; and the 500 mg dose group was superior to the 250 mg dose group, but the differences were not statistically significant (ORR: χ2=0.416, P=0.519; DCR: χ2=0.609, P=0.435). Long-term efficacy: the 500 mg dose group had a slight advantage over the 250 mg dose group in both median PFS time (3.9 months vs. 3.6 months) and median OS time (7.8 months vs. 7.6 months), but the differences were not statistically significant (PFS: χ2=0.472, P=0.492; OS: χ2=0.261, P=0.609). Conclusions Low-dose apatinib can be used to treat advanced malignant tumors. The drug-related adverse reactions are small, the curative effects are exact, the adverse reactions are easy to tolerate, and it is convenient for long-term use. Low-dose apatinib is one of the treatment options for advanced malignant tumors. Key words: Malignant tumors; Apatinib; Low-dose; Adverse reactions

Acute adverse reactions observation of craniospinal irradiation with helical tomotherapy in patients with medulloblastoma

Objective To investigate the acute adverse reactions of craniospinal irradiation with helical tomotherapy in medulloblastoma patients and its risk factors. Methods A total of 20 patients with medulloblastoma who received craniospinal irradiation with helical tomotherapy between October 2012 and September 2016 in Air Force General Hospital were selected. The acute adverse events of 20 patients during the treatment were record. According to National Cancer Institute Common Terminology Criteria Adverse Events (NCI-CTCAE) version 4.0, the adverse reactions were divided into the mild group (grade 0-Ⅱ) and severe group (grade Ⅲ-Ⅳ) adverse reactions. And the risk factors were also analyzed. Results The non-hematological adverse reactions included fatigue (55%), vomiting (45%) and headache (25%). The hematological adverse reactions included leukopenia (95%), thrombocytopenia (55%) and lower hemoglobin (45%), and the incidence of severe adverse reactions was 35% (7/20), 20% (4/20) and 0 (0/20), respectively. Leukopenia occurred in 18 patients (90%) at the beginning of radiotherapy within 2 weeks, and thrombocytopenia occurred in 8 patients (40%) at the beginning of radiotherapy after 2 weeks. Single factor analysis showed that there were no statistical differences in hematological adverse events of gender, age and radiation dose of spinal cord (all P > 0.05). The incidence of leukopenia for the patients who received the chemotherapy before the radiotherapy was higher than that for the patients without the chemotherapy before the radiotherapy (P < 0.05). Conclusions The hematological adverse reactions were the major acute adverse events during the craniospinal irradiation with helical tomotherapy in patients with medulloblastoma. The incidence of leukopenia and thrombocytopenia is common, and the incidence of hematological adverse reactions is higher after the chemotherapy. Thus, the close monitoring of hemogram change and treatment of hematological adverse reactions in time during the radiotherapy should be taken into the consideration. Key words: Medulloblastoma; Tomography, spiral computed; Adverse reactions

A retrospective analysis of the efficacy and safety of imatinib in children with chronic myeloid leukemia during chronic phase

Objective: To evaluate the efficacy and safety of imatinib in the treatment of newly diagnosed chronic myeloid leukemia during chronic phase (CML-CP) in children and to analyze the difference of the efficacy and safety between imported original imatinib (Gleevec) and domestic generic imatinib (Xinwei). Methods: Clinical data of 35 children with newly diagnosed CML-CP in Beijing Children's Hospital from January 2014 to January 2018 were collected, among which 15 cases were treated with the imported original imatinib (original drug group) and 20 cases were treated with the domestic generic imatinib (generic drug group). The hematological, cytogenetic and molecular reactions and safety of the treatments were monitored at months 3, 6 and 12. Chi square test or rank sum test was used for the comparison between two groups. Results: A total of 35 cases were treated for over 3 months, 31 cases were treated for over 6 months and 25 cases were treated for over 12 months. At 3 months, main cytogenetic response was obtained in 15 (100%) cases in the original drug group and 16 (80%) cases in the generic drug group respectively (χ(2)=3.387, P=0.119). At 6 months, complete cytogenetic response was obtained in 12 (80%) cases in the original drug group and 10 (63%) cases in the generic drug group (χ(2)=1.435, P=0.390). At 12 months, BCR-ABL(IS) ≤ 0.1% was obtained in 11 (92%) cases in the original drug group and 10 (77%) cases in the generic drug group (χ(2)=1.009, P=0.593). There was no significant difference at all stages (all P>0.05). Hematologic toxicity occurred in 7(20%) cases. The non-hematologic adverse reactions include nausea in 8 (23%) cases, pain in 8 (23%) cases, edema in 6 (17%) cases, emesis in 2 (6%) cases, fever in 2 (6%) cases, weakness in 1 (3%) case, rash in 1 (3%) case. The adverse reactions were easy to control and no drug toxicity related deaths occurred. There was no significant difference in the adverse reactions between original drug group and generic drug group (P>0.05). Conclusions: Imatinib had a good efficacy and safety in the early treatment of newly diagnosed CML-CP in children. The efficacy and safety of generic imatinib is similar to that of imported imatinib.

Prospective Clinical Study of Capecitabine plus Oxaliplatin Concurrent Chemoradiotherapy after Radical Resection of Rectal Cancer

To investigate the efficacy and safety of concurrent chemoradiotherapy with capecitabine or oxaliplatin in locally advanced (T3-4 / N + M0) rectal cancer. A total of 56 patients with rectal cancer after radical operation were randomly divided into group A: capecitabine + oxaliplatin concurrent chemoradiotherapy group (Cap-Oxa-CRT trial, 30 cases), group B: capecitabine concurrent chemoradiotherapy group (Cap-CRT trial as Control group, 26 cases), both groups were given pelvic radiotherapy DT50.4Gy/28f/6 weeks. The two groups received adjuvant chemotherapy after concurrent CRT. (1) The 3-year overall survival rate, 3-year local recurrence rate and 3-year distant metastasis rate were not significantly different between the two groups (P> 0.05). (2) The incidence of grade 1-2 acute toxicity in group A during concurrent CRT was significantly higher than that in group B, the difference was statistically significant (P <0.05). Grade 3 toxicities were not statistically significant between the two groups (P> 0.05). No grade 4 toxicity was found in both groups. The incidences of interrupted or suspend concurrent chemotherapy in both groups were 19.23% and 46.67%, respectively, P <0.05. The incidences of interruption or suspension of radiotherapy were 11.54% and 30% respectively (P> 0.05). The completion rate of adjuvant chemotherapy in group B was higher than that in group A, but the difference was not statistically significant (P> 0.05). In postoperative adjuvant chemotherapy, the incidence of bone marrow suppression in group A was higher than that in group B (P <0.05), and the incidence of non-hematologic adverse reactions was similar between the two groups. Capecitabine combined oxaliplatin concurrent CRT, and oxaliplatin concurrent CRT have a good effect for treatment of patients with locally advanced rectal cancer after radical resection of rectal cancer. However, group A failed to further improve the curative effect, and its grade 1-2 toxicity increased significantly.

Prospective clinical study of capecitabine plus oxaliplatin concurrent chemoradiotherapy after radical resection of rectal cancer

BackgroundTo investigate the efficacy and safety of concurrent chemoradiotherapy with capecitabine or oxaliplatin in locally advanced (T3-4/N + M0) rectal cancer.Methods56 patients with rectal cancer after radical operation were randomly divided into CAPE-OX-CRT group: capecitabine + oxaliplatin concurrent chemoradiotherapy (30 cases), CAPE-CRT group: capecitabine concurrent chemoradiotherapy (control, 26 cases).ResultsThe incidence of grade 1–2 acute toxicity in CAPE-OX-CRT group during concurrent CRT was significantly higher than that in control group, the difference was statistically significant (P < 0.05). Grade 3 toxicities were not statistically significant between the two groups (P > 0.05). No grade 4 toxicity was found in both groups. The incidences of interrupted or suspend concurrent chemotherapy in both groups were 19.23% and 46.67%, respectively, P < 0.05. The incidences of interruption or suspension of radiotherapy were 11.54% and 30% respectively (P > 0.05). The completion rate of adjuvant chemotherapy in control group was higher than that in CAPE-OX-CRT group, but the difference was not statistically significant (P > 0.05). In postoperative adjuvant chemotherapy, the incidence of bone marrow suppression in CAPE-OX-CRT group was higher than that in control group (P < 0.05), and the incidence of non-hematologic adverse reactions was similar between the two groups.ConclusionCapecitabine combined oxaliplatin concurrent CRT, and oxaliplatin concurrent CRT have a good effect for treatment of patients with locally advanced rectal cancer after radical resection of rectal cancer.

Phase I multicenter, open-label study to establish the maximum tolerated dose (MTD) of trifluridine/tipiracil (TAS-102) and oxaliplatin combination in patients (pts) with metastatic colorectal cancer (mCRC).

816 Background: Preclinical evidence suggests improved efficacy when combining trifluridine/tipiracil with oxaliplatin compared to each monotherapy (Nukatsuka, 2015). The primary objective was to determine the MTD and the safety profile of the doublet among mCRC pts who have progressed after at least one prior line of treatment. Methods: Using a 3+3 design, eligible pts received escalating trifluridine/tipiracil doses from 25, 30 to 35 mg/m² bid, days 1–5 q14, together with a fixed dose of oxaliplatin 85 mg/m² (day 1). An intermediate cohort with a lower dose of oxaliplatin (65 mg/m²) plus 35 mg/m² of trifluridine/tipiracil was also tested. Results: Fifteen of 17 enrolled pts were evaluable for DLTs. Median age was 61 years (range 32-74), 11 and 6 pts had an ECOG PS of 0 and 1, respectively; 76% received ≥2 lines including for 10 pts previous line with oxaliplatin. Pts received a median of four cycles (range 1–23). The MTD was defined at the maximal planned dose: trifluridine/tipiracil 35 mg/m² bid, oxaliplatin 85 mg/m². Combination was well tolerated and only one DLT was observed (grade 3 febrile neutropenia). The most common ( &gt; 20%) non-hematologic adverse drug reactions (ADRs) included nausea, asthenia, vomiting, diarrhea and decreased appetite. Moderate-to-severe neutropenia occurred in 5 pts and thrombocytopenia in 4 pts (all grade 1); 1 pt experienced a grade 4 anemia at Cycle 4. Oxaliplatin-related neurotoxicity grade ≥2 was observed in 2 pts. ADRs were manageable with basic supportive care, with treatment delays or temporary interruptions. Best overall response includes partial response (n = 1, unconfirmed), stable disease (n = 7). Conclusions: At the MTD (trifluridine/tipiracil 35 mg/m² bid, oxaliplatin 85 mg/m²), incidence and severity of bone marrow suppression as well as gastrointestinal toxicities were similar to previously published data. A cohort of 6 additional pts will confirm the MTD. An expansion part combining the doublet with either nivolumab or bevacizumab evaluating the safety and preliminary antitumor activity of each triplet will start soon. Clinical trial information: NCT02848443.

Efficacy observation of GDP regimen for treatment of relapsed and refractory non-Hodgkin lymphoma

Objective To analyze the efficacy of GDP regimen for treatment of relapsed and refractory non-Hodgkin lymphoma (NHL). Methods The clinical data of 40 patients with relapsed and refractory NHL in the Third Hospital of Peking University from January 2009 to June 2014 were retrospectively analyzed. All the patients underwent GDP regimen (gemcitabine, dexamethasone, cisplatin). The clinical features, laboratory data and survival status were analyzed. Results The overall response rate (ORR) of 40 patients was 67.5% (27/40) with 27.5% (11/40) complete remission (CR) rate and 40.0% (16/40) partial remission rate. The 3-year overall survival (OS) rate was 86.5% and the OS rate of 5-year was 28.8%. The ORR and 3-year OS rate in B-cell lymphoma and T-cell lymphoma were 69.6% (16/23) vs. 52.9% (9/17) (P= 0.283), 90.9% vs. 80.7% (P= 0.480). The CR rate in patients with gastrointestinal tract involvement was better than that in patients without gastrointestinal tract involvement (P= 0.049). Meanwhile, the patients with gastrointestinal tract involvement were superior in 3-year OS rate (89.3% vs. 76.2%, but the difference was not statistically significant (P= 0.237). The major side effect was hematological adverse reactions. The incidence of grade Ⅲ/Ⅳ neutropenia was 47.5%, the rate of Ⅲ/Ⅳ thrombocytopenia was 40.0% and the rate of Ⅲ/Ⅳ anemia was 17.5%. Non-hematological adverse reactions included mild nausea and vomiting. Conclusions GDP regimen is effective and well tolerated in relapsed and refractory NHL with better efficacy for gastrointestinal tract involvement NHL patients. Key words: Lymphoma, non-Hodgkin; Recurrence; Refractory; Antineoplastic combined chemotherapy protocols; Efficacy; Adverse reactions

Clinical Efficacy of Low-dose Decitabine Combined with CAG Regimen in Patients with Myelodysplastic Syndrome-refractory Anemia with Excess Blasts(MDS-RAEB)

To investigate the clinical efficacy of low-dose decitabine combined with CAG regimen in patients with myelodysplastic syndrome-refractory anemia with excess blasts (MDS-RAEB) through retrospective analysis. Thirty-six patients with MDS-RAEB who ever received low-dose decitabine combined with CAG regimen were enrolled into decitabine + CAG group and 40 patients with MDS-RAEB treated by decitabine alone in our center were enolled into the control group. The clinical characteristics, efficacy and adverse reactions (AE) were compared between the 2 groups. Compared with the control group, the overall response rate (ORR) [complete remission (CR)+partial remission (PR) + hematologic improvement (HI) rate] of the decitabine+CAG group was higher (83.3% vs 62.5%)(P=0.043), and the AEs were not significantly increased. Cytopenia grade ≥3 and infection after treatment were the most prevalent AEs, which occurred in the early stage (within the first 2 cycles) and gradually decreased later. Other non-hematologic AEs were infrequent. Low-dose decitabine combined with CAG regimen has better clinical efficacy for patients with MDS-RAEB than that of decitabine alone. It is worthy to be applied in clinic, especially for these patients who are not ineligible for hematopoietic stem cell transplantation.

Efficacy and safety of tyrosine kinase inhibitor in treating elderly patients with chronic myeloid leukemia during chronic phrase

Objective To evaluate the efficacy and safety of tyrosine kinase inhibitors (TKI) in treating the elderly patients with chronic myeloid leukemia (CML) during chronic phrase. Methods From January 2015 to January 2016, a total of 52 cases of chronic phrase CML patients who received TKI treatment, over 60-year-old and were treated at Department of Hematology, West China Hospital were included in this study. Thirty-three cases of them chose imatinib (IM) as the first-line treatment regimen and 2 cases of them chose nilotinib (NIL) as the first-line treatment regimen, while the other 17 cases were treated with interferon before IM. The therapeutic response, overall survival (OS), event-free survival (EFS), comorbidity and drug-related adverse reactions of all the patients were analyzed by retrospective method, in order to summarize the efficacy and safety of TKI in the treatment of CML in elderly patients. Results ① The rates of cumulative complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR) and major molecular response (MMR) were 100.0% (52/52), 82.7 % (43/52), 80.8 % (42/52) and 71.2 % (37/52), respectively. The rates of OS of 1-year, 5-year and 10-year were 100.0%, 95.1% and 75.3%, respectively, while the rates of EFS of 1-year, 5-year and 10-year were 92.3%, 73.3% and 51.4%, respectively. ② Twenty-five patients had comorbidities. The scores of Charlson comorbidity index (CCI) of these 52 patients were all less than 2 scores. There were no significant differences in the incidence of cumulative CCyR, MCyR, MMR, grade Ⅲ hematologic and non-hematologic adverse reactions between 32 patients with CCI score=0 and 20 patients with CCI score>0 (χ2=0.948, 0.525, 0.021, 0.288, 0.021; P>0.05). ③ In 50 patients who received treatment of IM, the incidence rates of Ⅲ-Ⅳ grade neutropenia, thrombocytopenia and anemia were 16.0 % (8/50), 28.0% (14/50) and 18.0% (9/50), respectively. While 14 patients occurred Ⅲ-Ⅳ grade non-hematologic adverse reactions, with the incidence rate of 28.0% (14/50). Due to intolerance of IM, 5 cases (10.0%, 5/50) of the patients received the second-line TKI treatment. Conclusions TKI is an effective and safe treatment for the elderly patients who have chronic phrase CML. Mild comorbidities have no influence on the therapy. Key words: Leukemia, myelogenous, chronic, BCR-ABL positive; Tyrosine kinase inhibitor; Aged; Drug-related side effects and adverse reactions; Comorbidity

Inducing therapy of cytarabine combined with daunorubicin or idarubicin for the newly diagnosed acute myeloid leukemia: comparison of clinical efficacy

Objective To explore the clinical effect and toxicity of daunorubicin combined with cytarabine(DA regimen)and idarubicin combined with cytarabine(IA regimen)for the treatment of patients with acute myeloid leukemia(AML)as induction chemotherapy. Methods The clinical data of 84 newly diagnosed AML patients(except M3)treated with DA or IA regimen were analyzed retrospectively. DA regimen group included 32 patients(17 males and 15 females with median age of 46 years), while IA regimen group included 52 patients(29 males and 23 females with media age of 49 years). Efficacy index was complete remission(CR), total efficiency and adverse reactions after one course of chemotherapy rate. Results In DA regimen group,the CR rate was 65.6 %(21/32), and the total efficiency rate was 75.0 %(24/32), while in IA regimen group, the CR rate was 71.2 %(31/52), and the total efficiency rate was 80.8 %(42/52), respectively,but, the differences of media survival and 5-year survival rate were not statistically significant(16.8 months vs. 24.9 months, 26 % vs. 44 %, both P>0.05). The main side effect in the two groups included hematologic(bone marrow suppression)and non-hematologic adverse reactions, with no significant difference between the two groups(all P>0.05). Conclusion For newly diagnosed AML patients, remission rate and total efficiency of DA regimen are same as IA regimen after one course treatment, and adverse events between the two regimens do not differ significantly. Key words: Leukemia, myeloid, acute; Daunorubicin; Idarubicin; Cytarabine; Induction chemotherapy

Single Arm, Multi-Center, Phase II Study Of Clofarabine In Chinese Pediatric Patients With Refractory Or Relapsed Acute Lymphoblastic Leukemia

BackgroundClofarabine is a second generation purine nucleoside which inhibits DNA polymerase alpha and ribonucleotide reductase, leading to the depletion of intracellular deoxynucleotide triphosphate pools, disruption of mitochondrial function and apoptosis. A phase II study was conducted to evaluate the safety and efficacy of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL) in China. MethodPatients aged 1-21 years with histologically confirmed, relapsed and/or refractory ALL were eligible. Clofarabine was administered intravenously for 5 days at 52 mg/m2/d during induction and consolidation. The primary end point was overall remission rate (ORR; complete remission [CR] plus CR with incomplete counts [CRi]). Blood samples were obtained from patients who agreed to blood drawing for pharmacokinetic determinations. ResultsA total of 44 patients were treated in this study, in which 43 were evaluable for response. The median age was 13 years (range: 5 to 22 years), and the majority were B cell-ALL (75%, 33/44). The overall remission rate was 44.2% (19/43), including two complete remissions (CR), and 17 CRis. 39 patients had progressive disease at cut-off time, the overall median remission duration was 2.9 months, and the median remission duration was 3.4 months for patients achieved CR or CRi. Seven CR/CRi patients had chance to got HSCT after clofarabine treatment. Subgroup analysis showed that patients younger than 14 years and with B cell-ALL had a higher ORR than patients older than 14 years and with T cell-ALL, and the difference were statistically significant (age < 14 years vs. age ≥14 years: 60.9% vs. 25%, p =0.0308; B cell-ALL vs. T cell-ALL: 57.6% vs. 0, p=0.002). The most common (≥10%) adverse reactions (ADR) were hematological toxicity, gastrointestinal reaction, and abnormal liver function, and the most common grade 3/4 non-hematologic ADRs was ALT elevation (13.6%). PK analysis demonstrated that after multiple administrations the mean elimination half-life of clofarabine was 6.43 h, and the Tmax was around 2 h. The mean Cmax and exposure to clofarabine over the dosing period (AUC 0-24) achieved 581 ug/L and 2602.56 ug/L, respectively. It seems that there is no significant difference of PK profiles between Chinese and Caucasian patients. ConclusionSingle clofarabine treatment is effective in Chinese pediatric patients with multiple relapsed or refractory ALL with acceptable safety profiles. Disclosures:No relevant conflicts of interest to declare.

Imatinib, dasatinib and nilotinib: a review of adverse cutaneous reactions with emphasis on our clinical experience

In the last years, several tyrosine kinase inhibitors (TKIs) have been developed and approved for human cancer treatment. Imatinib mesylate was the first of this novel family of drugs that target cancer-specific molecules and signalling pathways. The appearance of imatinib resistances led to the introduction of second-generation TKIs with higher potency and selectivity, such as dasatinib and nilotinib. However, the range of activity of these agents is not simply directed at tumour cells. Patients and their clinicians are indeed frequently confronted with the cutaneous side-effects associated with the employ of these drugs, which represent the most common non-hematological adverse reactions. For this reason, a systematic dermatological survey of patients receiving these therapies is highly important, and an early and appropriate dermatological treatment is required. In this review, we analyse the clinical and pathological characteristics of the most commonly reported adverse skin events associated with first- and second-generation tyrosine kinase inhibitors, with a particular emphasis on our clinical experience.

Multiple TKIs approved in recent months

Evolution of TKIs Patients with CML and ALL Imatinib (Gleevec—Novartis) was approved more than a decade ago as a targeted leukemia therapy (i.e., Bcr-Abl TKI). Since that time, researchers have uncovered much information regarding its resistance mechanisms and potential ways to overcome resistance. Imatinib resistance reportedly occurs in approximately 33% of patients and can be subclassifi ed as Bcr-Abl–dependent or Bcr-Abl–independent. The BcrAbl–dependent mechanisms involve Bcr-Abl mutation and amplifi cation, resulting in an alteration of imatinib’s binding affi nity to the Bcr-Abl tyrosine kinase. One of the most frequently identifi ed mutations is T315l. Second-generation TKIs such as dasatinib (Sprycel—Bristol-Myers Squibb) and nilotinib (Tasigna—Novartis) are more potent than imatinib and can be used as fi rst-line agents for the management of chronic-phase CML as well as for imatinib-resistant or -intolerant patients. The new agent bosutinib is also classifi ed as a second-generation TKI. It targets the Bcr-Abl kinase and inhibits Scr-family kinases including Src, Lyn, and HcK. Pharmacologic data have shown that bosutinib inhibits 16 of 18 imatinib-resistant forms of Bcr-Abl kinases expressed in experiential cell lines. This agent, however, has no effect on T315I mutant cells. Ponatinib is classifi ed as a thirdgeneration TKI. The agent is unique in that it targets cells with a T315I mutation, which makes these cells resistant to all other currently approved TKIs. Medullary thyroid cancer Cabozantinib has a different indication and, therefore, targets another set of tyrosine kinases. It has been shown to inhibit proinvasive receptor tyrosine kinases implicated in tumor growth, metastasis, and angiogenesis, including RET, MET, and VEGFR-1, -2, and -3. Activating mutations in RET have been shown to play a central role in tumorigenesis in both inherited and sporadic forms of medullary thyroid cancer. MET and VEGF have also been implicated in the pathogenesis of this rare thyroid disease.

Long-term effect of interferon-α combined with homoharringtonine on chronic myelogenous leukemia in chronic phase

To evaluate the efficacy of interferon-α (IFN-α) combined with homoharringtonine (HHT) in the treatment of patients with newly diagnosed chronic-phase chronic myelogenous leukemia (CML), an IFN-α combined with HHT scheme was used as induction and maintenance therapy for 42 patients with CML in chronic phase. Thirty-five patients treated with IFN-α alone were used as the control group. It was found that the cytogenetic response rate and estimated 2-year survival rate were higher in the IFN-α + HHT group than in the IFN-α group (52.4% vs. 28.6% and 90% vs. 73%, respectively). No grade 3 or 4 hematological toxicity, severe infections, hemorrhage or non-hematological adverse reactions were observed. From this research it can be concluded that an IFN-α combined with HHT scheme is safe and effective for CML induction and long-term maintenance therapy. It may be a good choice for patients with CML who cannot accept a hematopoietic stem cell transplant and imatinib or who fail IFN-α therapy.

Generalized lichenoid drug eruption associated with imatinib mesylate therapy

Imatinib mesylate (IM), an anticancer drug, has been widely used to treat chronic myeloid leukemia (CML), gastrointestinal stromal tumors (GIST), and dermato-fibrosarcoma protuberans. Cutaneous reactions to IM have been reported to occur in varying number of patients in different case series. Non-lichenoid cutaneous reactions secondary to IM have been well-documented in the literature and are the commonest non-hematologic adverse reactions associated with its use. Lichenoid drug eruption (LDE) associated with IM therapy has rarely been reported in the literature. A case of a generalized LDE associated with IM therapy has been described here for its rarity and interesting clinical presentation. As the clinical usage of IM is increasing, one might expect an increasing number of similar patients in the future. It is thus important to realize the potential of IM to produce LDE and to differentiate this entity from idiopathic lichen planus. In the present article, the reports of IM-associated LDE, described in the PubMed and Medline database (in English language literature), have also been reviewed.

Efficacy and SAFETY of Dasatinib 50 MG Once Daily DOSE In PATIENTS with CHRONIC PHASE CML WHO Failed IMATINIB

Abstract 4440 Background:Dasatinib is multi-targeted kinase inhibitor and it is approved therapy for patients with imatinib-resistant or imatinib-intolerant CML or newly diagnosed CML (chronic phase). The recommended dosing regimen is Dasatinib 100 mg once daily (QD), based on results from the CA180-034 dose-optimization study in patients with CML-CP and resistance or intolerance to prior therapy and it is active against the vast majority of BCR/ABL mutations apart from T315I and can overcome emerging resistance. Aims:to assess the efficacy and safety of 50 mg once daily dose of Dasatinib in achieving complete hematological remission (CHR),complete cytogenetic remission(CCYR) and major molecular response (MMR) in patients with CML-CP and resistance or intolerance to prior imatinib therapy. Patients and Methods:nine adult patients (aged ≥18 years) with prior imatinib failure were enrolled in this study after informed consent, between September and November 2009 and followed for 18 months. Received Dasatinib 50 mg once daily as second line therapy and were evaluated at baseline,3,6, 12, and 18 months as per European leukemia net(ELN) guidelines for response CHR, CCYR, MMR mutation analysis was not done because it is not available in our centre. Patients with baseline pleural effusion or ejection fraction less than 50% were excluded. Chest x-rays were performed at baseline and at 6 months, or more frequently if indicated clinically. Pleural effusions were graded according to CTCAE v3.0 criteria: grade 1, asymptomatic; grade 2, symptomatic, ≤ 2 therapeutic thoracenteses; grade 3, symptomatic requiring supplemental oxygen, > 2 therapeutic thoracenteses; grade 4, life-threatening, hemodynamic instability. Results:All patients achieved complete hematological as well as complete cytogenic response within three months and remains so at 6 and 12 months assessment, 18 months assessment for molecular response showed that 8 out of 9 achieved major molecular response and one patient achieved complete molecular response, grade two or more toxicity were not seen in any patient. Anemia and neutropenia Grade ≥ 2 were not observed in any patient, thrombocytopenia grade one was observed in one patient. Non-hematologic adverse drug reactions like fluid retention; including pleural effusion, nausea vomiting, myalgia, muscle inflammation and rash were not observed in any patient. Conclusion:In patients with chronic phase chronic myeloid leukemia who failed first generation TKI (Imatinib). Dasatinib 50 mg once daily is safe, effective and capable of achieving complete hematological and cytogenetic remissions well as major molecular response‘ with better toxicity profile keeping in consideration the small number of patient's further studies are needed to confirm this result. Disclosures:No relevant conflicts of interest to declare.

Phase II Study of Combined Treatment with Irinotecan and S-1 (IRIS) in Patients with Inoperable or Recurrent Advanced Colorectal Cancer (HGCSG0302)

Objectives: This phase II study was designed to evaluate the efficacy and safety of oral fluoropyrimidine S-1 plus irinotecan (IRIS regimen) in patients with previously untreated metastatic colorectal cancer. Methods: The response rate was the primary endpoint. Safety, progression-free survival time, and median survival time were secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer. Irinotecan was administered at a dose of 100 mg/m² (on days 1 and 15). S-1 (40 mg/m²) was administered for 2 weeks (on days 1 to 14) and followed by a 2-week rest. Results: Forty patients were enrolled. Four patients had grade 4 neutropenia, and six patients had grade 3 diarrhea. No other serious hematologic or nonhematologic adverse reactions occurred, and all patients received IRIS safely on an outpatient basis. The response rate was 52.5% (95% confidence interval [CI], 36.1–68.5%). Median progression-free survival was 8.6 months (95% CI, 5.3–11.9), and median survival time was 23.4 months (95% CI, 15.9–30.8). Conclusions: IRIS produced a high response rate and could be given safely. IRIS may become a first-line treatment for inoperable or recurrent advanced colorectal cancer.

Dasatinib compared to imatinib (IM) in patients (pts) with newly diagnosed chronic-phase chronic myelogenous leukemia in chronic phase (CML-CP): Twelve-month efficacy and safety from the phase III DASISION study.

LBA6500 Background: Dasatinib is a highly potent BCR-ABL kinase inhibitor. Once daily dasatinib demonstrated high rates of durable complete cytogenetic response (CCyR) with 73% progression-free survival and 87% overall survival at 3 yrs in pts with CML-CP post IM failure. DASISION compares efficacy and safety of dasatinib and IM as initial treatment of CML-CP. Methods: 519 pts with Ph(+) newly diagnosed CML-CP stratified by Hasford risk were randomized to dasatinib 100 mg QD (n = 259) or IM 400 mg QD (n = 260). The primary endpoint was 12-mo rate of confirmed CCyR (cCCyR; CCyR on 2 consecutive analyses; any # of metaphases). Other endpoints were rates of and times to CCyR and major molecular response (MMR). Results: Pts characteristics were well balanced. Minimum follow-up was 12 mos; median treatment duration was 14 mos. 85% of dasatinib and 81% of IM pts remained on study. Median dose intensity was 99 mg/d for dasatinib and 400 mg/d for IM. cCCyR rate was superior for dasatinib vs IM (77% vs 66%, P = 0.0067). 12-mo CCyR and MMR rates ( Table ) were higher for dasatinib vs IM (CCyR: 83% vs 72%; MMR: 46% vs. 28%). MMR was obtained significantly faster with dasatinib (HR 2.0, P &lt; 0.0001) as was CCyR (HR 1.5, P &lt; 0.0001). Rates of transformation to AP/BC were 1.9% for dasatinib and 3.5% for IM. Grade 3/4 anemia (10% vs 7%) and neutropenia (21% vs 20%) were similar across arms; thrombocytopenia was more common for dasatinib (19% vs. 10%). Non-hematologic adverse drug reactions (all grades) in ≥10% of pts (dasatinib vs. IM) were fluid retention (19% vs 42%; including pleural effusion, all grade 1 or 2, 10% vs. 0%), nausea (8% vs. 20%), vomiting (5% vs. 10%), myalgia (6% vs.12%), muscle inflammation (4% vs. 17%) and rash (11% vs. 17%). Conclusions: Dasatinib showed significantly higher and faster rates of CCyR and MMR vs IM. Given the predictive value of 12-mo CCyR and MMR and the favorable tolerability of dasatinib, dasatinib may improve long-term outcomes in pts with newly diagnosed CML-CP. [Table: see text] [Table: see text]