Differences In Hematologic Toxicity Research Articles

Randomized Phase II Trial of Amrubicin Plus Irinotecan Versus Cisplatin Plus Irinotecan in Chemo-naïve Patients With Extensive-Disease Small-Cell Lung Cancer: Results of the Japan Multinational Trial Organization (JMTO) LC 08-01

BackgroundWe conducted a randomize phase II study to evaluate the efficacy and safety of topoisomerase II inhibitor amrubicin plus topoisomerase I inhibitor irinotecan (AI) compared with cisplatin plus irinotecan (PI) as first-line therapy in patients with extensive-disease (ED) small-cell lung cancer (SCLC). Patients and MethodsChemo-naïve patients with pathologically proven ED-SCLC (including limited disease (LD) SCLC with malignant effusion) were enrolled. Patients were randomized 1:1 to receive either AI (amrubicin 90mg/m2 on day 1 and irinotecan 50mg/m2 on days 1 and 8 of a 21-day cycle) or PI (cisplatin 60mg/m2 on day 1 and irinotecan 60mg/m2 on days 1, 8 and 15 of a 28-day cycle). The primary endpoint was overall survival proportion at 1 year. ResultsA total of 100 patients were randomly assigned to AI (n = 50) or to PI (n = 50). The 1-year overall survival proportions were 68.0% (95% confidence interval (CI): 56.2-82.2%) for AI and 59.2% (46.9-74.7%) for PI (1-sided P = .18). Median survival time was 14.8 months for AI and 13.5 months for PI with a hazard ratio (HR) of 0.618 (0.398-0.961, stratified log-rank test P = .031). Median progression-free survival time was 4.8 months for AI and 5.4 months for PI (stratified log-rank test, P = .54). Objective response rate was 70.0% (55.4-82.1%) for AI and 55.1% (40.2-69.3%) for PI (Fisher exact test, P = .15). There was no significant difference in hematological toxicity, whereas rates of vomiting, loss of appetite, diarrhea, and elevated serum creatinine are more frequent in PI. Interstitial lung disease (Grade 2 or 3) developed in 5 patients in AI and in 1 patient in PI. There was no treatment-related death. ConclusionAlthough the study did not meet its primary endpoint, AI showed promising efficacy and good tolerability in chemo-naïve patients with ED-SCLC.

Safety outcomes of pembrolizumab with platinum agent chemotherapy combined with 5-fluorouracil or taxane derivative in head and neck cancer.

For patients with metastatic head and neck squamous cell cancer (HNSCC), the outcomes of pembrolizumab in combination with a platinum agent and taxane as first-line therapy remain unknown. The purpose of this study is to characterize the impact of substituting the 5-fluorouracil (5-FU) backbone for a taxane in this chemoimmunotherapy regimen on safety/tolerability and survival outcomes. This was an IRB-approved, single-center, retrospective, active comparator, new-user design study in adult patients with HNSCC treated between January 2018 and September 2021. The primary objective was to assess safety and tolerability of pembrolizumab in combination with a platinum agent and taxane against an active comparator arm of pembrolizumab in combination with a platinum agent and 5-FU. Safety and tolerability were evaluated by assessing differences in overall toxicities, with further secondary analysis evaluating differences in hematologic toxicities and pre-defined non-hematologic toxicities. There was no statistical difference demonstrated with the primary endpoint between the cohorts. Reduced toxicity rates were found in the taxane arm for mucositis and creatinine levels. No grade 4 non-hematologic toxicities were reported. Patients receiving 5-FU were more likely to have dose reductions upfront, discontinue treatment due to intolerances and had significantly higher mucositis. This study helps to characterize the safety profile and activity of pembrolizumab in combination with a platinum agent and taxane derivative in HNSCC patients. Within our study, substitution of 5-FU with a taxane did not show an increased risk of toxicities, worsened survival, or decreased odds of achieving a response. Mucositis and elevated creatinine rates were significantly reduced within the taxane arm.

Treatment Patterns, Toxicity, and Outcomes of Older Adults With Advanced Pancreatic Cancer Receiving First-line Palliative Chemotherapy.

Advanced pancreatic cancer (APC) disproportionately impacts older adults. Randomized trials demonstrate improved overall survival (OS) with combination chemotherapy including 5-fluorouracil, irinotecan, leucovorin, and oxaliplatin (FOLFIRINOX) or nab-paclitaxel and gemcitabine compared with gemcitabine alone, but with increased toxicity. Older adults are at increased risk of side effects from chemotherapy. The aim of this study was to assess the efficacy and toxicity of chemotherapy in older adults with APC. Patients diagnosed with APC from 2011 to 2016 were identified using the Manitoba Cancer Registry. Patient and treatment characteristics, toxicity, and outcomes of patients 65 years of age and above treated with palliative chemotherapy were compared by treatment regimen. OS was assessed using the Kaplan-Meier method. A Cox regression was used to identify independent predictors of OS. A total of 87 patients aged 65 years and above received palliative chemotherapy: 52 (59.7%) FOLFIRINOX, 21 (24.1%) nab-paclitaxel and gemcitabine, and 14 (16.1%) gemcitabine, with a median age of 69 (65 to 84), 75 (65 to 88), and 73 (67 to 82), Eastern Cooperative Oncology Group (ECOG) performance status difference in hematologic toxicity between regimens (P=0.807). An increase in nonhematologic toxicity was seen with FOLFIRINOX (P<0.001), specifically neuropathy (P=0.008), fatigue (P<0.001), and nausea/vomiting (P=0.008). FOLFIRINOX was associated with improved radiologic response (P=0.05) and OS (P=0.035). PS, baseline carbohydrate antigen 19-9 level, and chemotherapy regimen were independent predictors of survival. FOLFIRINOX is associated with improved response and OS in older adults with APC. FOLFIRINOX has a manageable safety profile in this population and should be considered in fit older adults with APC.

Role of thoracic radiotherapy in extensive stage small cell lung cancer: a systemic review and meta-analysis.

BackgroundThe role of thoracic consolidation radiotherapy in patients with extensive stage small cell lung cancer (ES-SCLC) remains controversial. This study aimed to evaluate the efficacy of thoracic radiotherapy (TRT) in these patients.MethodsA systematic literature search was performed in PubMed, Embase, and the Cochrane library to identify qualified clinical studies. The hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS), progression-free survival (PFS) and local recurrence-free survival (LRFS) were extracted, and toxicity of the TRT group versus non-TRT group was analyzed.ResultsA total of 12 studies were included in this meta-analysis, including 936 patients in the TRT group and 1,059 patients in the non-TRT group. The combined results showed that TRT significantly improved OS (HR =0.65; 95% CI: 0.55–0.77, P<0.00001), PFS (HR =0.64; 95% CI: 0.56–0.72, P<0.00001) and LRFS (HR =0.38, 95% CI: 0.26–0.53, P<0.00001). Subgroup analysis showed that OS benefits were observed in patients receiving sequential TRT (HR =0.67; 95% CI: 0.54–0.84, P=0.0006). The addition of TRT significantly improved OS in patients over 65 years of age (HR =0.55; 95% CI: 0.40–0.74, P=0.0001). For patients with only one organ metastasis, there was no significant difference in OS between the two groups (HR =0.61; 95% CI: 0.36–1.01, P=0.06). There was no statistical difference in hematologic toxicity (leukopenia, thrombocytopenia, anemia) and non-hematologic toxicity (nausea or vomiting) between the two groups. The incidence of grade ≥3 esophageal toxicity was 4.6% in the TRT group and 0% in the non-TRT group (P=0.0001). Grade ≥3 bronchopulmonary toxicity was 2.9% in the TRT group and 0.8% in the non-TRT group (P=0.02).ConclusionsTRT improves OS, PFS and LRFS in patients with ES-SCLC, with a low increase in esophageal and bronchopulmonary toxicity. More randomized controlled trials (RCTs) are expected to confirm our conclusions.PROSPERO registration numberCRD42020190575.

Ethnic Differences in Hematologic Toxicity from Imatinib in Patients with Gastrointestinal Stromal Cell Tumor (GIST): Coincidence or a Real Phenomenon.

Objectives:There is a wide variability in the pharmacokinetics, pharmacodynamics and tolerance of anticancer drugs based on ethnicity. GIST is a rare cancer, (~1% of GI cancers). Imatinib is used in the neo-adjuvant, adjuvant and metastatic setting. The purpose of this study was to report the difference in hematologic toxicities to imatinib among different ethnicities when treated for GIST either in the adjuvant or metastatic setting.Methods:We performed a retrospective study to collect data on patients with GIST (in any stage), who were on imatinib and presenting with grade 2 or more anemia, neutropenia and/or thrombocytopenia from July 1, 2005 to January 31, 2018. The degree of cytopenia was graded as per National Cancer Institute Common Toxicity criteria; version 4.0. We collected included age, gender, ethnicity, pathology, adverse effects-hematologic and non-hematologic, management of toxicities including dose modifications and administration of pegfilgrastim.Results:Among 57 patients (median age 61 years, M: F=41:16 (F); ethnicities: White 65%, African-American (AA 19%, Asian 12% and Hispanic 4%), neutropenia (Grade 3 & 4) was seen in 6 patients (10%): 5 AA and 1 Asian. 45% of all AA patients developed neutropenia. Median absolute neutrophil count (ANC) nadir was 700/μL, median duration on drug prior to onset of neutropenia was 4.5 weeks and median duration of neutropenia was 4 weeks. One patient developed febrile neutropenia. Dose interruptions were needed in 3, dose-reductions in all patients, and 3 patients required pegfilgrastim. One patient had to discontinue imatinib, while one patient was escalated back to 400mg daily dose.Conclusion:This is the first study to examine ethnic variations in myelosuppression following imatinib in patients with GIST.

Treatment patterns, toxicity, and outcomes of elderly patients with advanced pancreatic cancer receiving first-line chemotherapy.

71 Background: Advanced pancreatic cancer (APC) has a poor prognosis despite treatment with palliative chemotherapy. Randomized trials have demonstrated improved overall survival (OS) with combination chemotherapy including 5-fluorouracil, irinotecan, leucovorin, and oxaliplatin (FOLFIRINOX) or nab-plaxictaxel and Gemcitabine (NG) compared to Gemcitabine (GEM) alone, however, combination therapy is associated with higher rates of toxicity. There is limited data regarding the efficacy and toxicity of FOLFIRINOX, NG, and GEM in elderly patients with APC. Objective: Describe the treatment patterns, toxicity, and outcomes of patients ≥ 65 years of age treated with first-line palliative FOLFIRINOX, NG, or GEM. Methods: Patients ≥ 65 diagnosed with APC from 2012-2016 and treated with palliative chemotherapy in Manitoba were identified from the Manitoba Cancer Registry. Retrospective review identified patients who received first line FOLFIRINOX, NG, or GEM. Patient and treatment characteristics including hematologic and non-hematologic toxicities, dose reductions or delays, tumour response and survival were recorded. Results: 87 patients aged ≥ 65 received palliative chemotherapy: 52 (60%) FOLFIRINOX, 21 (24%) NG, and 14 (16%) GEM, with median ages of 69 (65-84), 75 (65-88), and 73 (67-82), respectively. More patients treated with FOLFIRINOX had an ECOG 0-1 compared to other treatments (p = &lt; 0.001). There was no difference in hematologic toxicity according to treatment group (p = 0.807). There was more non-hematologic toxicity with FOLFIRINOX (p = &lt; 0.001), particularly neuropathy (p = 0.008), fatigue (p = &lt; 0.001), and nausea/vomiting (p = 0.008). Tumour response was highest with FOLFIRINOX (p = 0.005), with a trend towards improved survival compared to NG and GEM (median OS 267 vs 232 and 126 days, respectively, p = 0.057). Conclusions: Many older patients with APC received FOLFIRINOX, with more toxicity, but also greater tumour response and a trend toward improved survival. This suggests that selected elderly patients can tolerate first-line FOLFIRINOX. This may be also due to effective patient evaluation and appropriate assignment to different treatments.

Ethnic differences in hematologic toxicity from imatinib in patients with gastrointestinal stromal cell tumor (GIST).

e23513Background: There is a wide variability in pharmacokinetics, pharmacodynamics & tolerance of anticancer drugs based on ethnicity. Myelosuppression is common in pts with cancer who receive che...

Effect of extending the original eligibility criteria for the “CROSS” neoadjuvant chemoradiotherapy on toxicity and survival in esophageal cancer.

187 Background: Patients with curable esophageal cancer (EC) which proceed beyond the original CROSS eligibility criteria are also treated with neoadjuvant chemoradiotherapy (nCRT). This study assessed the effect of extending the CROSS eligibility criteria for nCRT on treatment related toxicity and overall survival (OS) in EC. Methods: Included were 161 patients with locally advanced EC (T1N1-3/T2-4aN0-3/M0), treated with the CROSS schedule followed by esophagectomy. Group 1 (N = 90) consisted of patients which met the CROSS criteria and patients in group 2 (N = 71) met the extended eligibility criteria, i.e. including a tumor length of &gt; 8 cm (N = 23), &gt; 10% weight loss (N = 35), &gt; 2 – 4 cm extension in the stomach (N = 21), celiac lymph node metastasis (N = 13), and/or age &gt; 75 years (N = 2). We assessed the differences in hematologic toxicity (≥ grade 3) and 90-day postoperative mortality. Moreover, we assessed the prognostic value on OS with multivariate Cox regression analysis. Results: No difference was found in hematologic toxicity and 90-day mortality. The OS differed significantly (P = 0.003), with a median of 37.3 (95% CI 10.56 – 64.0) and 17.2 (95% CI 13.8 – 20.6) months in group I and II, respectively. Pathological N-stage (P = 0.024), ypT-stage (P = 0.044), and group II (P = 0.006) were independent prognostic factors for OS. Conclusions: Extension of the CROSS study eligibility criteria for nCRT did not affect hematologic toxicity and postoperative mortality, but was prognostic for OS.

3080 Polled analysis of nivolumab for the treatment of advanced non-small cell lung cancer and the role of PD-L1 as a biomarker

the combination of amrubicin and topoisomerase II inhibitor irinotecan has yet to be examined in randomized clinical trials. We conducted a randomize phase II study to evaluate the efficacy and safety of amrubicin plus irinotecan (AI) compared with cisplatin and irinotecan (CI) in chemonaive patients with extensive-disease (ED) SCLC. Material and Methods: Eligibility criteria included ECOG PS 0−2, age 20 or older, pathologically proven SCLC, ED (Limited disease (LD) with pleural effusion was also eligible), adequate organ function, and written informed consent. Patients were randomized 1:1 to receive either AI (amrubicin 90mg/m on day1 and irinotecan 50mg/m on days 1 and 8 of a 21-day cycle) or CI (cisplatin 60mg/m on day1 and irinotecan 60mg/m on days 1, 8 and 15 of a 28-day cycle). The AI regimen was based on the recommended dose of our previous phase I trial JMTO LC 03−03 (Kawahara M, et al. J Thorac Oncol 2011). The primary endpoint was overall survival (1-year survival rate). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety profile. Stratification factors are PS (0−1 or 2), LDH value (within normal limit or not), institution, and clinical stage (ED or LD with pleural effusion). Results: A total of 100 patients were randomly assigned to AI (n = 50) and to CI (n = 50). One patient was ineligible and excluded from analysis. One-year survival rate was 68.0% (95% confidence interval: 56.2–82.2%) for AI and 62.8% (50.5–78.0%) for CI (one-sided p = 0.29). The stratified log-rank test of two curves comparison showed p = 0.11. Median survival time was 14.7 months for AI and 14.2 months for CI with a hazard ratio (HR) of 0.69. Median PFS was 4.2 months for AI and 5.4 months for CI (stratified log-rank test, p = 0.91). ORR was 70.0% (55.4–82.1%) for AI and 55.1% (40.2–69.3%) for CI (Fisher exact test, p = 0.15). There was no significant difference in hematological toxicity, whereas rates of vomiting, loss of appetite, diarrhea, and elevated serum creatinine are more frequent in CI. Interstitial lung disease (Grade 2 or 3) developed in 5 patients in AI and in 1 patient in CI. There was no treatment-related death. Conclusions: Although the study did not meet its primary endpoint, the combination of amrubicin plus irinotecan showed similar efficacy to that of cisplatin plus irinotecan in chemo-naive patients with ED SCLC. Conflict of interest: Corporate-sponsored Research: Yakult Pharmaceutical Industry.

The effect of weight-based chemotherapy dosing in a cohort of gynecologic oncology patients

ObjectiveMany clinicians limit chemotherapy doses based on a maximum body surface area (BSA) of 2m2. We sought to determine how chemotherapy-related toxicities compared between groups of patients that varied with respect to BSA. We hypothesized that obese patients receiving weight-based (WB) dosing would not have significantly higher chemotherapy-related toxicities than control groups. MethodsWe performed a retrospective review of patients with BSA≥2m2 who received WB chemotherapy for a gynecologic cancer between January and August 2013. Subjects were matched with two controls: patients with BSA<2m2 who received WB dosing, and patients with BSA≥2m2 who received capped dosing at BSA=2m2. Groups were matched for medical co-morbidities and prior cancer treatment. Demographic and clinical information was extracted and analyzed via ANOVA and Fisher's exact test. ResultsA total of 75 patients were included. The three groups were similar in their medical co-morbidities and prior cancer treatment. When comparing pre- and post-treatment laboratory values, there was no difference in hematologic toxicities. There was no difference between groups with regard to treatment delays, unplanned admissions, transfusions, or dose reductions for toxicity. ConclusionsGynecologic cancer patients with BSA≥2m2 treated with WB chemotherapy had no increase in hematologic or non-hematologic toxicities when compared to controls. Consideration should be given to using WB dosing in obese patients with gynecologic malignancies. Further investigation is required to determine the effect of WB dosing on progression-free and overall survival in obese gynecologic cancer patients.

Chemotherapeutic Response and Prognosis among Lung Cancer Patients with and without Depression.

Purpose: The current study examined quality of life, progression of disease, and survival rate during chemotherapy in newly diagnosed non-small cell lung cancer (NSCLC) patients with depression (n=48) and without depression (n=78). Further, the study explored the hypothesis that the survival benefit resulted from the chemotherapy of docetaxel and cisplatin (the DC regimen).Patients and Methods: In total, 126 patients with newly diagnosed NSCLC participated in a cross-sectional study of DC chemotherapy integrated with standard oncology care in depression and non-depression groups. The health-related quality of life (HR-QOL) was assessed using the quality of life questionnaire for Chinese cancer patients receiving chemobiotherapy (QLQ-CCC). Depression was self-rated using the Zung Self-Rating Depression Scale (Z-SDS). Both HR-QOL and Z-SDS were completed before the first and after the last cycle of chemotherapy. Association between depression and quality of life, treatment responses, adverse effects and survival rate was considered positive at the significance level of p<0.05. Pearson and Spearman correlation coefficient, t-test and other statistical analysis were performed using the SPSS software version 13.0 for Windows.Results: In total, 126 lung cancer patients were evaluated, 38% had a diagnosis of depression. The presence of depression was associated with reduced quality of life, increased progression of disease, nausea and fatigue and reduced survival rate by nearly 90 days on follow-up. Therefore, depression significantly predicted worse survival (P=0.009).In addition, the chemotherapy DC regimen did not appear to improve the quality of life in depressed patients (SDS 94.96±18.14 before chemotherapy vs. SDS 100.04±16.61 after therapy, P=0.155). In a secondary analysis, there was a positive relationship between depression and nausea and fatigue but there was no significant difference in hematologic toxicities between the depression and non-depression groups.Conclusion: Depression was associated with worse survival in patients with newly diagnosed NSCLC. Also, the chemotherapy DC regimen did not improve quality of life in depressed patients and the data do not support the hypothesis that treatment responses of NSCLC patients with depression mediated the observed survival benefit from the DC regimen. There were more cases of progressed disease in the depressed group. Findings suggest that NSCLC patients with depression are at increased risk for decline in HR-QOL and survival rate during chemotherapy than patients without depression.

S-1 plus CIK as second-line treatment for advanced pancreatic cancer

This study aimed to evaluate the efficacy and tolerability of S-1 (Tegafur, Gimeracil, and Oteracil Potassium Capsules) plus CIK (Cytokine-induced killer cells) in patients with advanced pancreatic cancer who had previously received gemcitabine-based therapy. In this prospective study, fifty-eight patients were randomly divided into two groups. One group (CT group) was given S-1 alone, and the other group (immuno-CT group) was given S-1 plus CIK. S-1 was administered orally twice a day at 80 mg/m(2)/day on days 1-21 of a 28-day cycle till disease progression or unacceptable toxicity occurred. CIK was given for one cycle of 28 days. The disease control rate for S-1 and CIK was 40.0 and 53.6%, respectively (p = 0.621). The serum CA19-9 level decreased for more than 25% was significantly different (33.3 and 60.7 % in CT group and immuno-CT group, respectively, p = 0.037). The median time to progression was 2.5 (95% CI 2.3-2.8) and 2.9 (95% CI 2.6-3.2) months (p = 0.037) for CT group and immuno-CT group, respectively. The median overall survival was 6.1 (95% CI 5.7-6.5) and 6.6 (95% CI 6.1-7.1) months (p = 0.09) for CT group and immuno-CT group, respectively. The difference in hematological toxicity, including leukocytopenia, anemia, and neutropenia, was insignificant between the two groups. In contrast, the differences in non-hematological toxicity, fatigue, and non-infective fever were significantly different between the two groups (p < 0.05). The S-1 plus CIK regimen was well tolerated in a second-line setting in patients with gemcitabine-refractory and advanced pancreatic cancer.

The HB22.7 Anti-CD22 Monoclonal Antibody Is an Effective Platform for CD22-Targeted Antibody Drug Conjugates for Treatment of Lymphoma and Acute Lymphoblastic Leukemia

AbstractAbstract 1653Many non-Hodgkin lymphomas (NHL) and acute lymphoblastic leukemia (ALL) initially respond to therapy, but relapse; at that point further treatment is often limited by chemotherapy-related toxicity. CD22 is a valid target for immunotherapy of NHL and ALL. We have shown that the anti-CD22 ligand blocking monoclonal antibody (mAb), HB22.7, has significant activity. Antibody drug conjugates (ADC) are emerging as the next generation of targeted therapies for lymphoid neoplasms as they may be designed to be effective but with manageable toxicity. We sought to determine if HB22.7 could be used as a platform for CD22-targeted ADCs for the treatment of lymphoid neoplasms. We describe here the effect H22.7-saporin (SAP), a novel ADC composed of HB22.7 and a ribosome inactivating protein on ALL and NHL models.The in vitro cytotoxicity of HB22.7-SAP was assessed using two pre-B cell ALL lines REH and JM1, and NHL cell lines Ramos, Raji, Granta 519, SU-DHL-4, and DOHH-2. HB22.7-SAP had IC50 values of 0.7 and 1.2 ng/mL in ALL and 1.0–8.4 ng/mL in the NHL cell lines. Free HB22.7 plus SAP did not have any cytotoxic effect using the same doses. HB22.7-SAP was not cytotoxic to CD22 negative Jurkat cells.To evaluate HB22.7-SAP’s in vivo efficacy against a model of human ALL, NOD/SCID mice were injected with REH leukemia cells. Twenty-four hours later the mice were treated with PBS, free HB22.7 plus SAP, or HB22.7-SAP. Treatment was continued twice weekly for 4 weeks. Mice were euthanized at the onset of hind limb paralysis. The median survival was 52 days as compared to 20 days for the untreated mice (p < 0.0005). Mice treated with HB22.7-SAP had normal blood counts over the study period. In contrast, mice from the PBS or free HB22.7 plus free SAP groups developed leukopenia and thrombocytopenia by day 20, coincident with development of ALL; bone marrow from the two mice that developed hind limb paralysis confirmed ALL.To assess efficacy in a human model of NHL, Raji cells were injected into the flank of previously radiated, female, athymic nude mice. Tumors grew until they reached 100–200 mm3 (day 0). Mice were then exposed to HB22.7-SAP, PBS, or free HB22.7 plus free SAP. Each treatment was administered intraperitoneally, weekly for 3 weeks. To assess significance of starting tumor volume on HB22.7-SAP-mediated tumor growth inhibition, a second model initiated therapy 24 hours after tumor implantation and used the same dose and drug schedule. During the first 14 days, HB22.7-SAP (1 mg/kg) significantly inhibited tumor growth (p < 0.01) on days 5 and 8 as compared to the PBS and free HB22.7 plus free SAP control groups, however, by day 19, the average tumors volume of mice treated with HB22.7-SAP were no different than the controls. In contrast, when HB22.7-SAP was administered 24 hours after subcutaneous injection of Raji cells no mice in the treatment group developed measureable tumors in the 50-day study period. There was no difference in hematologic toxicity between the groups however mice treated with HB22.7-SAP had more therapy-related weight loss.This study demonstrates the promising in vivo and in vitro activity of HB22.7 when used as a platform for CD22-targeted ADCs. The HB22.7-SAP ADC is both specific and cytotoxic to CD22 expressing malignant lymphocytes and that translates into significant efficacy against NHL and ALL. When compared to other anti-CD22 mAb we hypothesize that HB22.7-based ADCs will prove to be potent cytotoxic drugs in-part due to their unique ability to block ligand binding thus conferring an independent lymphocidal property. Disclosures:No relevant conflicts of interest to declare.

Gender Difference in Hematological Toxicity Among Lung Cancer Patients Receiving Amrubicin Monotherapy

Severe hematological toxicity has been frequently observed during amrubicin monotherapy for patients with lung cancer despite the favorable anti-tumor response. The purpose of this retrospective study was to identify pretreatment factors associated with severe hematological toxicity. The medical records of lung cancer patients treated with amrubicin monotherapy were reviewed, and univariate and multivariate analyses were conducted. From January 2003 to December 2006, the medical records of 103 patients were extracted. Grade 4 neutropenia was frequently observed in females (male, 66% and female, 90%, P = 0.036 in a univariate analysis). In a multivariate analysis, female gender (P = 0.019), body weight loss (P = 0.021) and amrubicin dose (P = 0.028) were significantly correlated with Grade 4 neutropenia. Gender could be considered as one of the important predictive factors associated with Grade 4 neutropenia in patients receiving amrubicin monotherapy.

A comparison of hematologic toxicity profiles after heated intraperitoneal chemotherapy with oxaliplatin and mitomycin C

BackgroundAlthough peritoneal carcinomatosis (PC) from colorectal and appendiceal tumors is consistent with metastatic disease, complete cytoreduction with hyperthermic intraperitoneal chemotherapy (HIPEC) using mitomycin C (MMC) can improve survival. A recent phase I study by our group using hyperthermic intraperitoneal oxaliplatin has demonstrated its safety and appropriate dose. Our goal in this study is to present a single institution’s experience with the hematologic toxicities of the two agents. MethodsWe performed a retrospective review of 187 patients with PC of colorectal or appendiceal origin who underwent HIPEC with MMC or oxaliplatin between October 2006 and September 2009. Hematologic toxicities were graded according to the NCI Common Terminology Criteria for Adverse Events Version 4.0. ResultsOf the 187 patients, 55 had oxaliplatin-based HIPEC while 132 patients received MMC. Splenectomy was performed in 95 patients (50.8%) due to disease involvement. When comparing hematologic toxicity for MMC and oxaliplatin among the cohort of patients who underwent splenectomy, a statistically significant difference was noted in the incidence of platelet (P = .02) and neutrophil (P = .05) toxicity, with oxaliplatin having a higher incidence of grade 3 and grade 4 platelet and neutrophil toxicity respectively. However, no statistically significant difference in hematologic toxicity was noted between the two agents in patients who did not undergo splenectomy during cytoreductive surgery. ConclusionsOxaliplatin-based HIPEC for PC of colorectal and appendiceal origin is associated with similar white blood cell toxicity and higher platelet and neutrophil toxicity compared to MMC-based HIPEC.

Ethnic Difference in Hematological Toxicity in Patients with Non-small Cell Lung Cancer Treated with Chemotherapy: A Pooled Analysis on Asian versus Non-Asian in Phase II and III Clinical Trials

There are a large number of global clinical trials ongoing for patients with non-small cell lung cancer (NSCLC). Ethnic difference in toxicity has not been adequately studied. We performed a systematic search in PubMed for randomized phase II and III trials of NSCLC from January 2000 to December 2009, examining ethnic difference in hematological toxicity due to cytotoxic chemotherapy. Ethnicity was classified into Asian and non-Asian. We chose three treatment regimens used for NSCLC globally: cisplatin plus gemcitabine (CG), cisplatin plus vinorelbine (CV), and carboplatin plus paclitaxel (CP). We applied sensitivity analysis to examine unreported ethnic differences in hematological toxicities by changing the percentage of Asian patients from 0 to 18% in trials reported from the United States and Europe. We identified 12 phase II trials and 38 phase III trials of NSCLC with a total of 11,271 patients. Among these, 14 trials had reported ethnic origins. Grade 3/4 toxicities were more frequently observed in the Asian studies. On the basis of sensitivity analysis, odds ratio of grade 3/4 neutropenia was significantly higher in Asian patients than non-Asian, when treated with CG (OR = 1.55-3.45, p < 0.001), CV (OR = 2.99-4.43, p < 0.001), and CP (OR = 4.79-6.22, p < 0.001). Grade 3/4 anemia was also significantly higher in Asians with CG (OR = 3.10-3.27, p < 0.001), CV (OR = 1.99-2.43, p < 0.001), and CP (OR = 1.34-1.52, p < 0.001-0.004). However, no significant difference was observed in thrombocytopenia with CG (OR = 0.66-2.04, p < 0.001-1.000), CV (OR = 0.42-0.57, p = 0.097-0.323), or CP (OR = 1.21-1.39, p = 0.114-0.152). Severe hematological toxicity was frequently observed in Asian patients compared with non-Asian (mostly whites) in the treatment of chemotherapy for NSCLC.

Primary Clinical Research of FA Regimen as Consolidation Therapy for Patients with Acute Myeloid Leukemia

AbstractAbstract 4380In our study, 28 patients with AML treated in our department between 2004 and 2009 under complete remission, median age of 54 years (range 23–77) were consolidated with FA regimen which included fludarabine 30mg/m2 (days 1–3) and Ara-C 2g/m2 (days 1–3). Ara-C were administered as a continuous sequential infusion 4 hours later when the application of fludarabine had been over. Another 14 AML patients with matched conditions treated with high dose Ara-C (HDAra-C, 3g/m2, q12h×3d) were designated as controls. Event-free survival of both 2 groups of these patients were analysed.Overall, 14 patients (50%) achieved continuous complete remission for more than 2 years. There is no statistically significant differences between FA group and HDAra-C group (P=0.214>0.05) in CCR. Patients aged >60 years also had no statistically significant differences compared to the patients aged <60 years in CCR. Seven patients relapsed after this treatment in a median survival of 11 months. Two of the relapsed patients had karyotype abnormalities and all of them had a markedly elevated WBC count at diagnosis.The main toxicity was myelosuppression. WBC count and platelet count reached the lowest (about 0.8×10^9/L and 2.0×10^9/L) 6–13 days after the begining of the regimen. Median recovery time for granulocyte (≥1.0×10^9/L) and platelet (≥20×10^9/L) was 12 and 13 days, respectively. Fever(>38°C) caused by granulopenia occurred in 21 patients, recovered to normal for a median time of 5 days (range, 2–23). Heart, liver and enteric toxicity were negligible. There were no significant differences in hematologic toxicity or nonhematologic toxicity between the FA and HDAra-C group. The average hospitalization was about 20 days.The FA is effective and safe as consolidation regimen in AML with acceptable toxicity and is not associated with an increased incidence of infections compared to conventional HDAra-C regimen. Disclosures:No relevant conflicts of interest to declare.

Randomized Phase III Trial Comparing ABVD + Radiotherapy and the Stanford V Regimen In Patients with Stage I/II Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the US Intergroup Trial E2496

AbstractAbstract 416 Background:Standard therapy for locally extensive Hodgkin Lymphoma (HL) defined as stage I/II with bulky mediastinal disease [mediastinal mass ratio (MMR) > than 1/3 of the chest diameter on standing postero-anterior chest x-ray or 10 cm on computerized tomography] is combined modality therapy (CMT). E2496 was a North American intergroup, randomized phase III study comparing ABVD versus the Stanford V regimen for patients with locally extensive and advanced stage HL. In this subgroup analysis we compare two CMT approaches, ABVD + radiotherapy (RT) and the Stanford V regimen, in patients with stage I/II bulky mediastinal HL. Methods:Patients with stage I/II HL bulky mediastinal disease were randomized to receive chemotherapy (CT) on either Arm A (ABVD × 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V, administered weekly). Two-3 weeks after completion of chemotherapy, modified involved field RT was delivered at 36 Gy to the mediastinum to patients on ABVD as well as Stanford V. Patients on Stanford V also received involved field RT to any other sites >5 cm at diagnosis. The primary endpoint was failure free survival (FFS) defined as the time to either progression/relapse or death. The log-rank test was used to compare FFS and OS (overall survival) for all eligible patients. Results:Of the 812 eligible patients with advanced HL enrolled on the study 267 had locally advanced bulky mediastinal disease: 136 on ABVD and 131 on Stanford V. Patient characteristics between the two randomized groups were well matched with a median age of 30 years and 86% had stage II disease. On ABVD 61% of patients received 6 cycles, 29% 8 cycles of CT and 77% required some dose modification. In Stanford V 97% completed the assigned 12 weeks of CT and 76% required some dose modification. 82% received RT per protocol in ABVD versus 88% in Stanford V. The overall response (CR+PR) was 82% in ABVD and 86% in Stanford V. At a median follow-up of 5.47 years, there are 19 failures and 6 deaths in the ABVD group and 25 failures with 9 deaths in the Stanford V group. We failed to detect statistically significant differences between ABVD +RT and Stanford V for FFS (5y 85% versus 77% p=0.13, HR=1.56 95% CI (0.87, 2.88) and OS (5y 95% versus 92% p=0.31, HR=1.69 95% CI (0.60, 4.75). No difference in hematologic toxicity was observed between the two arms. Evaluation of pulmonary function and patterns of failure are pending. Conclusions:For stage I/II patients with bulky mediastinal disease, CMT with either ABVD +RT or the Stanford V regimen results in high cure rates and is highly effective. ABVD for 6–8 cycles plus 36 Gy RT remains the US standard of care. Longer follow up is required to assess RT related late effects. Future research efforts should focus on risk stratification to identify; a) the 15–20% of patients destined to relapse after standard therapy and evaluate treatment intensification strategies and b) the 80–85% of patients who are cured with standard therapy and determine whether a subset can achieve the same excellent outcomes with a reduction or elimination of radiation. Planned US cooperative group trials will address these questions, using ABVD as the chemotherapy backbone in conjunction with interim PET imaging for risk stratification. Disclosures: Blum:Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.

Ethnic difference in toxicity in non-small cell lung cancer patients treated with chemotherapy: A systematic review on phase II and III clinical trials.

7638 Background: There are a large number of global clinical trials ongoing for patients with non-small cell lung cancer (NSCLC). Ethnic difference in toxicity has not been fully studied. Methods: We performed a systematic search of PubMed for phase II (PII) and phase III (PIII) trials of NSCLC from January 2000 to December 2009 to examine ethnic difference in hematological toxicity due to cytotoxic chemotherapy. Ethnicity was classified into Asian and non-Asian (mostly Caucasian). We chose the treatment regimens that were commonly used globally including carboplatin (CBDCA) plus paclitaxel (PTX), cisplatin (CDDP) plus gemcitabine (GEM), and CDDP plus vinorelbine (VNR) for NSCLC. Because ethnicity origins were not fully reported in the entire trials, we applied sensitivity analysis by changing the percentage of Asian patients from 5 to 15% in the trials reported from the United States and Europe. In these analysis, the percentage of toxicity in the Asian patients was settled as the mildest toxicity in the trials collected. Results: We identified 12 PII and 38 P III trials (11,271 patients), and the 14 trials had reported ethnicity origins. Grade 3-4 toxicities were more frequently observed in the Asian studies. Based on sensitivity analysis, odds ratio for the risk of grade 3 or greater toxicities (neutropenia and anemia) was higher in Asian. Although there was no significant association between median survival time (MST) and degree of neutropenia, MST was better in the Asian study (12.2 month vs. 9.6 months, p=0.012). Conclusions: Severe hematological toxicity was frequently observed in Asian patients compared with non-Asian (mostly Caucasian) in treatment of chemotherapy for NSCLC. Neutropenia Anemia Thrombocytopenia CBDCA + PTX,* odds ratio** 70.9% vs. 33.7%(p < 0.0001), 2.1-3.2 10.8% vs. 7.4%(p < 0.0001),1.2-1.4 8.8% vs. 6.5%(p = 0.11),1.1-1.2 CDDP + GEM,* odds ratio** 53.9% vs. 25.3%(p < 0.0001),1.1-1.7 24.7% vs. 9.2%(p < 0.0001),1.6-2.1 28.0% vs. 16.0%(p < 0.001),0.8-1.2 CDDP + VNR,* odds ratio** 77.2% vs. 36.7%(p = 0.02),1.9-3.0 23.9% vs. 10.0%(p < 0.0001),2.0-2.4 1.9% vs. 4.5%(p = 0.20),0.3-0.4 * Asian trials vs. non-Asian trials. ** Asian against non-Asian in sensitivity analysis. No significant financial relationships to disclose.

Bendamustine Plus Rituximab Is Superior in Respect of Progression Free Survival and CR Rate When Compared to CHOP Plus Rituximab as First-Line Treatment of Patients with Advanced Follicular, Indolent, and Mantle Cell Lymphomas: Final Results of a Randomized Phase III Study of the StiL (Study Group Indolent Lymphomas, Germany).

Abstract 405▪▪This icon denotes an abstract that is clinically relevant.Introduction: Promising results have been observed in two phase-II studies evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas (Rummel et al., JCO 2005; Robinson et al., JCO 2008). In order to further investigate the role of the combination B-R we initiated a multicenter randomized phase-III study in October 2003 to compare efficacy and safety of B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for patients with follicular (FL), indolent and mantle cell lymphomas (MCL).Patients and Methods: 549 patients (pts) in need of treatment for their disease were randomized to receive Rituximab 375 mg/m2 (day 1) plus either Bendamustine 90 mg/m2 (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was progression-free survival (PFS). Patients characteristics, including age, stage, LDH, IPI, FLIPI, bone marrow infiltration and extranodal involvement did not statistically significant differ between both arms. The median patient age was 64 years (range 31-83) (64 yrs for B-R and 63 yrs for CHOP-R). Most patients were in stage IV (76,9% in BR and 77,5 in CHOP-R) and stage III (19,2% in B-R and 18,6% in CHOP-R). Histologies were distributed equally between B-R and CHOP-R: follicular 55% and 56%, mantle cell 18% and 19%, and other indolent lymphomas 27% and 24%, respectively. Prophylactic use of antibiotics or growth factors were not generally recommended in this protocol.Results: Of the 549 pts 36 pts were not evaluable: 10 did not receive any study medication, 9 due to withdrawal of consent, 13 due to incorrect diagnosis (4 × DLBCL, 3 × CLL, 2 × MM, 1 × HD, 3 × solid tumors), and 4 for other reasons. 513 randomized pts are evaluable for the final analysis (B-R: n=260; CHOP-R: n=253). Out of these 9 pts were not evaluable for response evaluation: 4 pts (3 × CHOP-R, 1 × B-R) due to early death in neutropenic sepsis, 3 pts due to a subsequent change of therapy after severe toxicity in 1st cycle of CHOP-R, 1 B-R pt due to progress of disease, and 1 B-R due to early death. All patients were counted for evaluation of PFS, overall survival (OS), event-free survival (EFS; an event was defined by a response less than a partial response, disease progression, relapse, or death from any cause), and for time to next treatment (TTNT).A median number of 6 cycles was given in both treatment arms each. 82% of B-R pts and 86% of CHOP-R pts received 6 cycles. At the time of analysis in August 2009, the median observation time was 32 months. Overall response rate for pts treated with B-R was similar to the CHOP-R group (93,8% vs 93,5%, respectively). The CR rate was significantly higher with 40,1% for B-R compared to 30,8% for CHOP-R (p=0.0323). The median PFS, EFS and TTNT were significantly longer after B-R compared to after CHOP-R: PFS 54,8 months for B-R versus (vs) 34,8 months for CHOP-R (p=0.0002), Hazard Ratio (HR) 0.5765 (95% confidence interval (CI) 0.4292 to 0.7683); EFS 54 months for B-R vs 31 months for CHOP-R (p=0.0002, HR 0.6014 (95% CI 0.4515 to 0.7845); and TTNT median not yet reached in the B-R group vs 40,7 months in the CHOP-R group (p=0.0002; HR 0.5416, 95% CI 0.3897 to 0.7491). OS did not differ between both groups at this point of time. Thus far, 67 deaths have been observed (B-R: 34; CHOP-R: 33).CHOP-R treatment was more frequently associated with serious adverse events (SAE) (n=49 in B-R vs n=74 in CHOP-R). Significant differences in hematologic toxicities were observed for neutropenia grade 3+4 (BR 10,7% vs CHOP-R 46,5%; p<0.0001) and for leukocytopenia grade 3+4 (BR 12,1% vs CHOP-R 38,2%; p<0.0001). G-CSF was more often used in CHOP-R treated pts (20,0% of all cycles) than it was used in the B-R group (4,0%) (p<0.0001). The B-R regimen was better tolerated by the pts as evidenced by a lower rate of alopecia (15% (only grade 1) in B-R vs 62% CHOP-R), a lower number of infectious complications (95 in BR vs 121 in CHOP-R, p=0.0403), a lower incidence of peripheral neuropathy (B-R n=18; CHOP-R n=73; p<0.0001), and fewer episodes of stomatitis (B-R n=16; CHOP-R n=47; p<0.0001). Only drug-associated erythematous skin reaction (urticaria, rash) was more often seen with B-R (n=42) than with CHOP-R (n=23) (p=0.0122).Conclusions: In this final analysis the combination of Bendamustine plus Rituximab improves PFS and CR rates while showing a better tolerability profile. These promising results suggest that B-R does have the potential to become a new standard first-line treatment option for patients with FL, MCL, and indolent lymphomas. Disclosures:Rummel:Roche Pharma AG: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Honoraria. Maschmeyer:OrthoBiotech: .