Single Course Of Chemotherapy Research Articles

Phase 2 study of combination chemotherapy with bortezomib in children with relapsed and refractory acute lymphoblastic leukemia.

Treatment outcomes for children with relapsed and refractory acute lymphoblastic leukemia (R/R-ALL) remain poor, and the optimal induction therapy has not been determined. Bortezomib is a proteasome inhibitor that acts synergistically and additively with standard chemotherapy for ALL. We evaluated the efficacy and safety of combination chemotherapy with bortezomib in children with R/R-ALL. This single-arm, multicenter, phase 2 study was conducted in Japan between 2016 and 2020. Eligible patients were divided into two cohorts: a high-risk first-relapse cohort of untreated patients with high-risk first-relapsed ALL and an expansion cohort of patients with refractory ALL, including multiple relapses, relapse after allogeneic hematopoietic cell transplantation, and induction failure. All patients received a single course of chemotherapy as induction therapy. Sixteen patients (10 in the high-risk first-relapse cohort, six in the expansion cohort) were evaluable. The overall remission rate after induction therapy was 60% in the high-risk first-relapse cohort and 16.7% in the expansion cohort. All patients had minimal residual disease. Adverse events were acceptable except for interstitial lung disease and hypoxia in a patient in the expansion cohort, but addition of bortezomib to conventional chemotherapy did not produce obvious improvement in children with R/R-ALL.

Development of a Novel Next-Generation Sequencing (NGS)-Based Assay for Measurable Residual Disease (MRD) in FLT3-ITD AML and Its Potential Clinical Application in Patients Treated with Chemotherapy Plus FLT3 Inhibitors

The presence of MRD in patients with acute myeloid leukemia (AML) who are in morphologic remission has been shown to be a powerful predictor of eventual relapse. FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) confer a negative prognostic impact by increasing the risk of relapse. However, the ability to detect these mutations in remission bone marrow specimens is hampered by the limited sensitivity of conventional polymerase chain reaction (PCR)-based assays, which detect approximately only 1 of every 100 (1%) mutant cells. To address this problem, we have developed a novel NGS-based MRD assay for the detection of FLT3-ITD mutations.Using isolated genomic DNA from bone marrow aspirates or whole-blood samples, PCR primers flanking exons 14 and 15 of the FLT3 gene were designed and highly diverse NGS libraries were generated. These libraries were then sequenced by Illumina's sequencing-by-synthesis method. The bioinformatics approach we used identifies unique FLT3-ITD mutations of varying length along with wild type sequences and calculates a mutant allelic frequency. The assay was validated using clinical samples to assess accuracy and reproducibility. DNA samples from selected mutant cell lines representing different FLT3-ITD lengths were spiked into normal DNA to evaluate assay sensitivity and linearity. The assay was linear (R2 = 0.958) down to FLT3-ITD allele frequency levels of 0.035% but was capable of detecting FLT3-ITD mutations at a level as low as 0.003%.We next validated the assay using clinical samples from patients with FLT3-ITD AML. The negative prognostic impact of FLT3-ITD mutations can be mitigated in part when an FLT3 inhibitor is administered in combination with induction chemotherapy, as demonstrated in CALGB10603/RATIFY (N Engl J Med. 2017;377:454). It was reported in this study that patients treated with an FLT3 inhibitor combined with chemotherapy followed by allogeneic transplant in first remission had better overall survival than their counterparts in the control arm. One hypothesis for this outcome is that the FLT3-inhibitor-treated patients had a lower leukemic burden prior to transplant. As a pilot test of this concept, we used our MRD assay on a series of bone marrow aspirate samples collected from 10 patients with newly diagnosed FLT3-ITD AML. The patients were selected to be as uniform as possible. All patients had intermediate-risk karyotype, a detectable FLT3-ITD mutation by conventional PCR, and mutated NPM1. All patients received cytarabine-based intensive induction and achieved morphologic first remission with a single course of chemotherapy. Finally, all patients underwent allogeneic transplant in first remission. The sample analyzed for MRD was the first collected after remission induction, 5-8 weeks after the start of therapy. The investigators performing the MRD assay were blinded to the clinical data. Four patients received chemotherapy alone, while 6 were treated with chemotherapy (7+3) plus an FLT3 inhibitor. In all patients' remission samples, the MRD assay identified the FLT3-ITD mutation that precisely matched the one observed in the original diagnostic specimen. This demonstrates the sensitivity of the assay (all samples had a detectable mutation), and the unique length of each patient's mutation confers a degree of specificity not achievable with MRD detection methods that focus on other AML-associated mutations. Supporting our hypothesis was the observation that patients treated with FLT3 inhibitors had MRD levels lower than those in patients treated with chemotherapy alone (Figure).Our results help establish the role of NGS-based MRD assays for the clinical management of FLT3-ITD AML. This assay could be used to define the depth of remission, identify persistent disease, and help guide decision making in the use of FLT3 inhibitors as continuation therapy. This study provides validation of the clinical utility of our MRD assay, which will be used to analyze the remission samples from patients in the ongoing phase 3, randomized, double-blind, placebo-controlled QuANTUM-First clinical trial, in which patients with newly diagnosed FLT3-ITD AML are randomized to receive either the highly potent and selective FLT3 inhibitor quizartinib or placebo in combination with chemotherapy, followed by single-agent quizartinib as continuation therapy. [Display omitted] DisclosuresShi:Novartis: Employment, Equity Ownership; Daiichi Sankyo: Other: Provide clinical trial testing services. Chang:Daiichi Sankyo: Employment. Laing:Novartis: Employment; Daiichi Sankyo: Other: Provide clinical trial testing services. Berisha:Daiichi Sankyo: Employment. Adams:Johns Hopkins University: Employment. Ding:Navigate BP: Employment; Daiichi Sankyo: Other: Provide clinical trial testing services. Nakamaru:Daiichi Sankyo: Employment. Lameh:Navigate BioPharma Inc,: Employment; Daiichi Sankyo: Other: Provide clinical trial testing services. Pollner:Navigate BioPharma Inc.: Employment. Kobayashi:Daiichi Sankyo: Employment.

A phase II study of irinotecan and pegylated liposomal doxorubicin in platinum-resistant recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 104 study)

PurposeWe report a phase II clinical study of the combination of irinotecan (CPT-11) and pegylated liposomal doxorubicin (PLD) in platinum- and taxane-resistant recurrent ovarian cancer, based on the recommended doses determined in a phase I trial.MethodsPLD was administered intravenously at a dose of 30 mg/m2 on day 3. CPT-11 was administered intravenously at a dose of 80 mg/m2 on days 1 and 15, according to the recommendations of the phase I study. A single course of chemotherapy lasted 28 days, and patients underwent at least 2 courses until disease progression. The primary endpoint was antitumor efficacy, and the secondary endpoints were adverse events, progression-free survival (PFS), and overall survival (OS).ResultsThe response rate was 32.3% and the disease control rate was 64.5%. Grade 3 and 4 neutropenia, anemia, and a decrease in platelet count were observed in 17 (54.9%), 3 (9.7%), and 1 patient (3.2%), respectively. In terms of grade 3 or higher non-hematologic toxicities, grade 3 nausea occurred in 1 patient (3.2%), vomiting in 3 patients (9.7%), and grade 3 diarrhea and fatigue in 1 patient (3.2%). The median PFS and OS rates were 2 months and not reached, respectively. Of the 11 patients with a treatment-free interval (TFI) of ≥3 months, the response rate was 63.3%, and the median PFS was 7 months.ConclusionsThe treatment outcomes for the 31 patients enrolled in this study were unsatisfactory. However, sub-analysis suggested that patients with a TFI of ≥3 months had a good response rate and PFS. This suggests that CPT-11/PLD combination therapy may be a chemotherapy option for platinum-resistant recurrent ovarian cancer.

Management of pure metastatic teratoma in chemotherapy naïve testis cancer patients.

e16043 Background: Management of metastatic testicular cancer often requires post-chemotherapy resection of teratoma. This is well known and described in literature. However, the ability of teratoma to metastasize independently is not as well appreciated, making chemotherapy futile in patients with pure metastatic teratoma. Methods: 15 patients with metastatic teratoma were identified of which 13 had only teratoma in the orchiectomy and 2 had predominantly teratoma. All 15 had normal serum hCG and AFP. Cases were derived from a retrospective review of patients seen from 1989-2016. Results: Mean age of patients was 27 years. 12 patients presented initially with Stage II disease and 2 presented with stage III disease. Median RP mass size was 6 cm with a range of 1.5-24 cm. 2 of 15 patients were treated initially with a single course of chemotherapy with BEP and showed no response. The remaining 13 patients only received resection(s). All 15 patients underwent RPLND with 2 patients requiring additional mediastinal and retrocrural resection and 1 requiring lobectomy. All surgical specimens showed pure teratoma on pathology with no other active germ cells. Patients were followed for a median duration of 5 years and all 15 remain with no evidence of disease at most recent follow up. However, 1 patient needed subsequent surgery for a late relapse of teratoma and 1 patient had a second extra-gonadal primary. Conclusions: Teratoma can metastasize in the absence of other germ cells. Surgical treatment alone for patients with pure metastatic teratoma of any stage can result in cure for the majority of patients and this approach can help avoid unnecessary chemotherapy.

The Impact Of European Leukemia Net (ELN) Genetic Classification On The Outcome Of Allogeneic Stem Cell Transplantation (ALLOHCT) For Acute Myeloid Leukemia (AML) In First Complete Remission

IntroductionThe improvements in genetic characterization of AML allowed the ELN to propose a prognostic classification into 4 categories: Favorable, Intermediate I, Intermediate II and Adverse. Several groups have tested the outcome of AML patients based on these genetic subgroups in registries and databases from prospective trials. Since ALLOSCT recommendations are being established based on the ELN risk categories, we considered of interest to investigate whether these also have an impact on the results of allogeneic transplants. This could be helpful to identify the patients that may benefit the most from ALLOHCT in the first complete remission (CR1). ObjectivesTo investigate whether the ELN genetic groups of AML have any impact on the results of ALLOHCT performed in CR1. To identify the patients who are best candidates for transplantation, based on the ELN categories as well as in other characteristics. MethodsPatients were transplanted between 1990 and 2012. In all cases, treatment prior to transplant had consisted of anthracycline based induction and intermediate-dose cytarabine consolidation according to the CETLAM AML-88, AML-94, AML-99 and AML-03 trials. Upper age limit for transplantation was 60 years until 2002 and 70 years thereafter. Most patients above 50 years received either CD34 selected grafts or reduced intensity conditioning. GVHD prophylaxis after transplant was usually based on cyclosporine and prednisone or methotrexate. The main characteristics of patients and transplants were included in the exploratory analysis of variables influencing survival; those with a p- value up to 0.1 were incorporated as covariates to the multivariable model. ResultsOne hundred ninety two patients in CR1 received an ALLOHCT from HLA-identical siblings (n=140), adult unrelated donors (n=26) or umbilical cord blood (n= 26). Age distribution of the patients was as follows: 16-35 years-old (y-o) n=65 (34%), 36-50 y-o n= 55 (29%), 51-60 y-o n= 54 (28%), >60 y-o n=18 (9%). Twenty-three patients (12%) were classified as in the favorable ELN category, 54 (28%) in the intermediate I, 41 (21%) in the intermediate II and 74 (39%) in the adverse. One-hundred fifty-seven patients (82%) had achieved CR1 after a single course of chemotherapy. Conditioning was myeloablative (MA) in 139 (72%) patients and reduced-intensity (RIC) in 53 (28%). In 76 cases of the MA regimens total body irradiation was included.Thirty-eight patients (20%) died due to transplant complications other than relapse and 47 (24%) experienced a leukemia recurrence. Overall survival (OS) and leukemia-free survivals at 8-years were 55±4% and 53±4%, respectively. Multivariate analysis of factors influencing OS included as covariates age at diagnosis of AML, ELN categories, courses to CR1 and conditioning regimen (MA versus RIC), since they had a p-value <0.1 in the univariate comparisons. The variables with independent on OS impact were age (p=0.01), courses to CR (p=001) and ELN classification (p=0.01). OS at 8 years in the favorable, intermediate I, intermediate II and adverse categories were 69±10%, 53±8%, 69±7% and 42±6%, respectively. In patients from the adverse ELN category, independent factors influencing OS in the multivariate analysis of this subgroup were age (16-60 y-o vs>60, p=0.01) and courses to CR (1 vs more, p=0.03). ConclusionsThe ELN genetic categories have impact on OS of AML patients who receive an ALLOHCT in CR1. The results were very good in the favorable category and, most important, in intermediate II patients. Even patients in the adverse category had a substantial probability of long-term survival. This is remarkable, since the outcome of patients with adverse genetic features when treated with CT only is very poor. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Haploidentical cellular therapy in elderly patients with acute myeloid leukemia: Description of its use in high risk patients

Guo et al. reported an innovative approach for the treatment of acute myeloid leukemia (AML) in a 2011 issue of Blood 1. The report showed for the first time that the infusion after chemotherapy of peripheral blood stem cells (PBSC) from haploidentical donors significantly improved the outcome in elderly AML patients, without major toxicities. After an initial engraftment, haploidentical donor cells are rejected by the host immune response. Indeed, the precise mechanism of action of this cell-therapy procedure is not fully understood and several mechanisms have been hypothesized to explain its beneficial effects: (i) donor allogeneic Natural killer (NK)- or T-cells might exert a direct cytotoxicity on leukemic cells; (ii) a proinflammatory effect of the allogeneic host–donor interaction might trigger an autologous antitumor immunity; and (iii) cell-therapy might induce modifications in leukemic cells or in stromal/vascular cells that ultimately elicit an autologous immune responses. So far, the data obtained, Guo et al. have not been confirmed by other groups worldwide. We recently treated with this protocol three elderly patients with high-risk AML. Compared to the Chinese experience, the patients were all affected by high-risk AML. As summarized in Table 1, Patient #1 had treatment-related AML following prolonged chemotherapy (six total lines) for ovarian cancer and her blasts had a mixed phenotype with complex karyotype. Patients #2 and #3 had AML with myelodysplasia-related changes, one of them (Patient #2) had received four azacitidine courses, with poor response and worsening of both hematological and clinical conditions. Institutional ethics approval was obtained for the use of this treatment protocol. All three patients received an induction regimen (a “3+7” regimen with mitoxantrone and ara-C) followed by the infusion of Granulocyte colony-stimulating Factor (G-CSF)-mobilized PBSC from haploidentical familial donors, according to the original protocol 1. The potential reactivity of patient T-cells against their haploidentical counterparts was proved in vitro by mixed lymphocyte reaction. This in vitro reactivity resulted in vivo in graft-rejection, with detectable microchimerism in only one patients and absence of acute or chronic Graft versus Host Disease (GVHD) in all patients. As detailed in Table 1, Patient #1 had a partial response, with Bone Marrow (BM) blast reduction from 90 to 45%. She then received an intensified salvage regimen (high-dose ara-C and idarubicin plus cyclosporine to overcome Minimal Residual Disease (MRD) resistance) 2, followed by a second infusion of haploidentical PBSC. After this cycle, she had a complete hematological recovery, and the BM aspirate showed complete remission of disease at flow cytometry. Six weeks later, AML relapsed; the patient was not further treated and died shortly thereafter. Patient #2 and #3 received 1 infusion of haploidentical PBSC after induction chemotherapy. Patient #2 was refractory, he refused further treatment and died few weeks later. Patient #3 achieved Complete Remission (CR); however, she was unable to receive consolidation therapy due to the development of fungal endophthalmitis and chronic sinusitis by Fusarium. She completely recovered within 3 months, with a mild residual chronic renal insufficiency. Despite lack of consolidation therapy, she is still in CR at 11 months of follow up. Our observation in high-risk elderly AML patients confirms that infusion of haploidentical-mobilized PBSC following induction chemotherapy is feasible and safe. Compared to Guo et al. 1, 3, we applied the strategy in AML patients with very unfavorable prognosis, two of them previously treated either with multiple chemotherapy lines or with repeated azacitidine courses. In spite of previous treatments, the haploidentical infusion did not induce acute GVHD. Considering the presenting features, the achievement of CR in two of three patients was encouraging and somehow unexpected, especially for the long-surviving patient who achieved CR after a single course of chemotherapy followed by haploidentical PBSC infusion. Finally, the two patients achieving CR had a leukothrombocytopenia duration shorter than one might have expected, suggesting a possible role of the infused cells in favoring hematopoietic recovery. We conclude that the “nonengraftment haploidentical cell-therapy” is feasible also in high-risk and previously treated AML patients, although the real efficacy in this setting needs to be further investigated 4. Indeed, based on our preliminary experience, a prospective trial will be launched soon to evaluate the procedure in elderly AML patients, including AML secondary to myelodysplasia, either untreated or after azacytidine, therapy-related AML as well as de novo AML A. Cignetti,1,2* M. Ruella,1,2 A. R. Elia,2 V. Tassi,3 V. Redoglia,4 D. Gottardi,1C. Tarella1,2 1University Division of Hematology and Cell Therapy, Mauriziano Hospital and University of Torino, Torino, Italy 2Molecular Biotechnology Center (M.B.C.), University of Torino, Torino, Italy 3Blood Bank, Molinette Hospital and University of Torino, Torino, Italy 4Division of Hematology, Molinette Hospital and University of Torino Torino, Italy

Erythropoiesis-Stimulating Agent (ESA) Practice Patterns in Patients With Chemotherapy-Induced Anemia (CIA) Treated at Hospital Oncology Clinics.

To characterize erythropoiesis-stimulating agent (ESA) usage initiated in hospital outpatient oncology centers that employ weekly (QW) and every-3-week (Q3W) ESA dosing regimens; describe the frequency of ESA dosing, transfusions, hemoglobin determinations, and anemia-related visits between these 2 regimens; and compare the rates at which inpatient ESA doses are administered on QW versus Q3W schedules. This was a retrospective, observational record review evaluating ESA usage in 641 patients from 8 outpatient oncology clinics throughout the United States. Adult patients who initiated myelosuppressive chemotherapy for a documented solid tumor between August 1, 2007 and June 30, 2009 and received their first 3 consecutive outpatient ESA doses on a QW or Q3W schedule were eligible for study inclusion. During a single course of chemotherapy, ESA administrations were recorded as long as ESA therapy was continued on the initial regimen. ESA doses were captured until termination of ESA therapy, until 9 months had elapsed since the first ESA dose, until the patient was switched to another ESA regimen, or until death. ESA administration during inpatient admissions was also recorded. ESA utilization varied between the dosing groups, with fewer ESA doses administered per follow-up month in patients receiving Q3W versus QW ESA therapy (mean, 1 vs 2 doses). Compared to weekly administration, extended-dose ESA therapy also reduced the number of hemoglobin determinations and anemia-related visits without chemotherapy required per follow-up month. Neither the number of transfusions nor the number of packed red blood cell units administered per follow-up month differed between treatment groups. Compared to weekly ESA therapy, Q3W administration reduced costs associated with ESA prescribing and utilization. Extended-dose ESA therapy (Q3W dosing) may improve practice efficiency and may be associated with reduced frequencies of hemoglobin determinations and ESA doses required. Q3W dosing may also reduce inpatient ESA utilization by reducing the number of ESA doses required for previously maintained outpatients.

A seven-year disease-free survivor of malignant pleural mesothelioma treated with hyperthermia and chemotherapy: a case report

IntroductionMalignant pleural mesothelioma was once a rare finding but its incidence is increasing worldwide, most likely because of widespread exposure to asbestos. Although complete surgical resection is considered the only curative treatment, the results of surgery have shown a median survival time of only one year. In inoperable cases, chemotherapy, radiotherapy, and a combination of both have been considered as palliative therapy. Therefore, outcomes for inoperable cases have been poor. Here, we report the case of a long-term survivor treated with hyperthermia and chemotherapy.Case presentationA 61-year-old Japanese man with a performance status of 1 due to chest pain was referred to our hospital. He had a history of asbestos exposure for approximately five years. A computed tomography scan showed diffuse extensive right pleural thickening with small nodular lesions, and video-assisted thoracoscopy revealed tumor invasion of the ipsilateral chest wall muscles. The histopathologic findings were consistent with a diagnosis of malignant pleural mesothelioma (sarcomatoid type). The tumor was diagnosed as being stage cT3N0M0. Our patient refused any invasive therapies including surgery and radiotherapy, and was therefore treated with hyperthermia and systemic chemotherapy with agents such as cisplatin and irinotecan. He underwent three hyperthermia sessions and a single course of chemotherapy without any severe complications. One month after treatment, a follow-up computed tomography scan showed no definitive abnormality in the thoracic space. Our patient has subsequently survived without any evident disease for more than seven years.ConclusionsThe combination of hyperthermia and chemotherapy may be a novel and safe therapeutic option for malignant pleural mesothelioma, and can be considered for patients ineligible for radical treatment. Further clinical studies of the combination of hyperthermia and chemotherapy are needed to confirm the effects of this treatment on malignant pleural mesothelioma.

Serial FDG–PET/CT for early outcome prediction in patients with metastatic colorectal cancer undergoing chemotherapy

The study purpose was to assess the predictive value of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)/computerized tomography (CT) metabolic response after a single course of chemotherapy in patients with metastatic colorectal cancer (mCRC). FDG-PET/CT scans were carried out at baseline and on day 14 in 41 patients with unresectable mCRC treated with a biweekly regimen of chemotherapy. Metabolic nonresponse was defined by <15% decrease in FDG uptake in the dominant proportion of the patient's lesions or if a lesion was found metabolically progressive. The PET-based response was correlated with radiological response (primary end point) and patient's outcome (secondary end points). RECIST response rate in metabolically responding patients was 43% (10 of 23) compared with 0% (0 of 17) in nonresponding patients (P=0.002). The metabolic assessment's predictive performance for RECIST response was sensitivity 100% [95% confidence interval (CI) 69% to 100%], specificity 57% (95% CI 37% to 75%), positive predictive value 43% (95% CI 23% to 66%), and negative predictive value 100% (95% CI 80% to 100%). Comparing metabolically responding versus nonresponding patients, the hazard ratio (HR) was 0.28 (95% CI 0.10-0.76) for overall survival and 0.57 (95% CI 0.27-1.21) for progression-free survival. The metabolic response measured by FDG-PET/CT after a single course of chemotherapy in mCRC is able to identify patients who will not benefit from the treatment.

Addition of Gemtuzumab Ozogamycin to Chemotherapy Improves Event-Free Survival but Not Overall Survival of AML Patients with Intermediate Cytogenetics Not Eligible for Allogeneic Transplantation. Results of the GOELAMS AML 2006 IR Study

Abstract 79The prognosis of acute myeloblastic leukemia (AML) with intermediate-risk cytogenetics is refined further by testing the mutational status of NPM1,FLT3 and CEBPa genes. Patients with a NPM1mut\\FLT3wt and CEBPa double mutation are now classified in a separate favorable group of the new ELN classification. Conversely, all other molecular profiles including these 3 genes, considered as carrying a worse prognosis, are included in ELN intermediate groups 1 and 2. Nevetheless the therapy of AML has remained unchanged since many years and needs improvement even in this subset of patients. The GOELAMS has tested the association of gemtuzumab ozozgamycin (GO), a monoclonal anti-CD33 antibody conjugated with chalicheamycin to standard chemotherapy in a phase III prospective randomized trial focusing on such patients with intermediate cytogenetics. Methods:Between 2007 and 2010, 254 patients aged between 18 to 60 years with de novo AML and intermediate karyotype have been included. The molecular status for NPM1, FLT3 and CEBPa mutations was determined at diagnosis. After 1/1 randomization, GO 6m/m2 was added to standard 3+7 induction and to a first MidAc intensive consolidation course (Mitoxantrone and intermediate doses of cytarabine). Patients in the ELN favorable molecular group received a second MidAc course followed by an autologous bone marrow transplant (BMT). Patients in the ELN intermediate 1 or 2 groups were considered for geno or phenoidentical allogeneic transplant. Patients 50 years of age or lower, received either standard allo-BMT preceded by a single course of chemotherapy or a reduced intensity chemotherapy (RIC) regimen after the two courses of intensive consolidation. In this sub-group, patients with no donor received autologous BMT after the two randomized courses of consolidation. Results:Two hundred and thirty-eight patients were analyzed with a median follow-up of 20 months. Their median age was 50 years old (18–60). There was no significant difference between the two arms according to age, WBC, % of circulating and % of marrow blasts, FAB subtypes, cytogenetics (normal vs abnormal) and molecular subgroups (favorable versus intermediate 1 and 2 ELN groups). In the GO group, the complete remission (CR) rate was 91.6% versus 86.5% (P=NS), early death(ED) was 10% versus 4.5% (P=NS). Major toxicity was observed in the GO arm during induction phase with 4 cases of veno-occlusive liver disease (VOD) and overall more toxic grade III/IV hepatic toxicities (23% versus 13%, p=0.031). No significant difference was observed between the two arms for grade III/IV hematological toxicity. No difference was observed either at 3 years for event free survival (EFS) at 51% in the GO arm and 33% in the other arm, nor for overall survival (OS) at respectively 53% and 46%. In the subset of patients who could not receive an allogeneic transplant, EFS was significantly higher in the GO group (53.7% vs 27%, p=0.0308) while there was no difference for OS. This better outcome was mostly observed in the group of patients classified ELN intermediate 1 or 2 (p=0.0126). Conclusion:In the subset of patients with intermediate cytogenetics AML, the adjunction of GO to standard chemotherapy failed to improved OS, yet a better EFS was observed with the addition of GO for patients who could not receive an allogeneic SCT. More detailed results will be presented. Disclosures:No relevant conflicts of interest to declare.

Serial FDG-PET/CT for early outcome prediction in patients with metastatic colorectal cancer undergoing chemotherapy.

3593 Background: The purpose of our study was to assess the predictive value of FDG-PET/CT metabolic response after a single course of chemotherapy in patients with metastatic colorectal cancer (mCRC). Methods: We performed two FDG-PET/CT scans (at baseline and on day 14) in 41 patients with unresectable mCRC treated with a biweekly regimen of chemotherapy. Patients were classified as metabolically non-responders when the dominant proportion of the tumor load showed a decrease in FDG uptake less than 15%, or if at least one lesion was demonstrated to be metabolically progressive. The PET-based response was correlated with RECIST-based response (primary endpoint), and progression-free and overall survival (secondary endpoints). Results: RECIST response rate in metabolically responding patients was 43% (10/23) compared to 0% (0/17) in metabolically non-responding patients (P=0.002). The predictive performance of the metabolic assessment for RECIST response was sensitivity 100% (95% CI, 69% to 100%), specificity 57% (95% CI, 37% to 75%), positive predictive value 43% (95% CI, 23% to 66%) and negative predictive value 100% (95% CI, 80% to 100%). Comparing metabolically responding versus non-responding patients, the hazard ratio was 0.28 (95% CI, 0.10 to 0.76, P=0.008) for overall survival and 0.57 (95% CI, 0.27 to 1.21, P=0.14) for progression-free survival. Conclusions: The metabolic response measured by FDG-PET/CT after a single course of chemotherapy in mCRC is able to identify the patients who will not benefit from the treatment.

The Cost Benefits of Early Detection

![Figure][1] CREDIT: ZEPHYR/PHOTO RESEARCHERS, INC In his News Focus story (“A bruising battle over lung scans,” 2 May, p. [600][2]), E. Marshall reports on the issue of screening smokers and patients at high risk for lung cancer with the use of computed tomography (CT)—an x-ray technique that visualizes internal structures in cross section. Opponents object to this procedure because it is “costly.” Although conventional x-ray screening was dismissed in the article, it is an economical first step, and if suspicious indications are seen, it should be followed by a CT scan. It is possible, or even probable, that this would allow early detection and surgical removal of the cancer followed by a single course of chemotherapy. This management is not costly compared with extensive, and often futile, chemotherapy at later stages of the disease. [1]: pending:yes [2]: /lookup/doi/10.1126/science.320.5876.600

Redefining the Role of Induction Chemotherapy in Head and Neck Cancer

Redefining the Role of Induction Chemotherapy in Head and Neck Cancer

Scoring System To Predict the Risk of Early Death during Induction Chemotherapy for Primary Acute Myeloid Leukemia (AML).

Complications during induction chemotherapy (CT) for AML cause mortality in 5–20% of cases. It is relevant to define the risk of early death in this setting. In patients with a high probability of dying due to toxicity, the intensification of the supportive measures and/or alternative antineoplastic approaches could be appropriate. The aim of this study was to detect the features associated with lethal complications during induction CT for AML. We defined early deaths (ED) as those occurring before 42 days after the start of induction in the absence of evident leukemia. We analyzed all consecutive patients diagnosed with AML between June 1998 and February 2006 in 20 Spanish hospitals. These cases were treated according two multicenter trials CETLAM 99 (n=326) and CETLAM 2003 (n=248). Both schemes included idarubicin 12 mg/m2 days 1,3 and 5, etoposide 100 mg/m2 days 1–3 and cytarabine 500 mg/m2/12 hours days 1, 3, 5 and 7 as front-line treatment. In the CETLAM 2003, G-CSF (150 mg/m2 days 0–7) was added as priming therapy. The series included 574 patients, 248 (43%) female, with a median age of 48 years. Creatinine level was elevated (> 1,2 mg/dL) in 11% of patients. The overall mortality rate during induction (ED) was 12% (n=69). 335 (58%) patients achieved a complete remission with a single course of CT, 108 (19%) a partial remission and 62 (11%) were refractory. The most common causes of death were infection (n= 28, 46%), bleeding (n=7, 11%), pulmonary failure not due to infection (n=6, 10%), and multiorgan failure (n=4, 7%). Univariate analysis showed that age older than 50 years old, male gender, M4 or M5 FAB subtype, leukocyte count higher than 100x109/L, blasts in the marrow >70% and creatinine level above 1,2 mg/dL were associated with more frequent ED. In multivariate analysis, elevated creatinine level [hazard ratio (HR) 2.6 (1.3–5.2); P=0.009], leukocytosis >100x109/L [HR 2.3 (1.1–4.6) P=0.021] and age > 50 years old [HR 2.1 (1.4–3.9) P=0.018] were independent risk factors. The remaining parameters, including among others the use of G-CSF, gender, blasts in the marrow, treatment protocol, cytogenetics at diagnosis and FLT-3 mutational status were not associated with higher incidence of ED. Taking into account the three significant variables identified as risk factors, we developed a scoring system to predict the probability of ED during induction. The probability of ED in the low risk (none risk factor, n=212), intermediate risk (1 risk factor, n=239) and high risk (2 or 3 risk factors, n=57) categories were 3%, 11% and 28% respectively (P<0.001). The HR of ED for patients in the intermediate and high risk groups were 3.6 (1.5–8.1, P=0.003) and 7.9 (3.1–19.7; P<0.001) as compared with the low risk group. In conclusion, impaired kidney function, advanced age and hyperleukocytosis are the relevant variables increasing mortality during induction CT for AML. With these three factors it is possible to define a scoring system which predicts the probability of ED. A different approach for patients in the high-risk group should be investigated.

Chemoradiation using low-dose cisplatin and 5-fluorouracil in locally advanced squamous cell carcinoma of the skin: A report of two cases

Recently, low-dose 5-fluorouracil/cisplatin induction concurrent with radiation (chemoradiation) has been reported to be effective for locally advanced squamous cell carcinoma of the otorhinolaryngologic and gynecologic regions. However, to date, this therapeutic option has not been evaluated for squamous cell carcinoma of the skin. We evaluated chemoradiation therapy using cisplatin and 5-fluorouracil in two patients with locally advanced squamous cell carcinoma of the skin. Administration of cisplatin and 5-fluorouracil was conducted concurrently with conventionally fractionated radiation therapy. Cisplatin (patient 1: 4 mg/m(2)/d on days 1 to 5; patient 2: 15 mg/m(2)/d on days 1 to 5) and 5-fluorouracil (patient 1: 400 mg/m(2)/d for 7 days; patient 2: 850 mg/m(2)/d for 5 days) were administered intravenously for 1 hour and for 24 hours, respectively. Patient 1 underwent two courses of chemotherapy with a 3-week interval, and patient 2 underwent a single course of chemotherapy. The primary tumor of both patients showed complete regression, leaving ulceration. In patient 1, the ulceration completely resolved after 3 months. Patient 2 underwent surgical resection and full-thickness skin grafting. A histopathologic examination confirmed complete tumor regression. Neither patient suffered any serious side effects during this treatment. We conclude that chemoradiation using cisplatin and 5-fluorouracil was effective in these two patients with locally advanced squamous cell carcinoma of the skin. Several randomized studies have shown concurrent chemoradiation to be superior to radiation alone. This regimen is an option in managing patients who have unresectable primary tumors or who require preservation of local function.

A prospective trial of short-course radiotherapy plus chemotherapy for palliation of dysphagia from advanced esophageal cancer

Purpose: Between 1994 and 1997, 22 patients with dysphagia from advanced incurable esophageal cancer were enrolled in a phase I/II prospective study to assess the palliative benefit and toxicity of a short course of radiotherapy with chemotherapy. Methods: The study population included 17 men and five women with a median age of 69 (range 43–84). Patients were treated with 30 Gy in ten fractions to the mediastinum with a concurrent single course of chemotherapy (5-FU, 1000 mg/m 2, days 1–4 and mitomycin-C 10 mg/m 2, day 1). Swallowing ability was recorded each day on a self-administered diary card using the five point dysphagia index of the MRC (UK). The median baseline MRC swallowing score was 4 (cannot swallow solids). Results: Treatment was generally well tolerated, but seven (32%) patients had transient worsening of dysphagia scores immediately following treatment because of esophagitis; fifteen (68%) achieved a complete response (score 1: no difficulty on swallowing) with a median time to normalization of swallowing of 5 weeks. For these patients, the median dysphagia-free interval from time of onset of improvement was 11 weeks (range 1–131 weeks) and 11 (73%) remained dysphagia-free until death.. The remaining patients had no or marginal improvement. Univariate analysis showed no difference between responders and non-responders with respect to age, gender, or histology. Median survival for the entire study population was 20 weeks (range 3–135 weeks). Conclusions: This prospective trial shows that a short course of radiotherapy plus chemotherapy may produce complete relief of swallowing difficulties in a substantial proportion of patients with acceptable toxicity.

A new form of Filgrastim with sustained duration in vivo and enhanced ability to mobilize PBPC in both mice and humans

Granulocyte colony-stimulating factor (G-CSF) has proven effective in the prophylaxis of chemotherapy-induced neutropenia and as a mobilizer of peripheral blood progenitor cells. The longevity of G-CSF action is limited by its removal from the body by two mechanisms. The first is thought to be mediated via receptors (receptor mediated clearance [RMC]) predominantly on neutrophils, the second process is likely the result of renal clearance. With the intention of developing a novel form of Filgrastim (r-met HuG-CSF) with a sustained duration of action in vivo, a new derivative named SD/01 has been made by association of Filgrastim with poly(ethylene glycol). The desired properties of this new agent would include a prolonged duration of action sufficient to cover a complete single course of chemotherapy. SD/01 is shown here to sustain significantly elevated neutrophil counts in hematopoietically normal mice for 5 days. In neutropenic mice effects were noted for at least 9 days, accompanying a significant reduction in the duration of chemotherapy induced neutropenia. Normal human volunteers showed higher than baseline ANC for around 9 to 10 days after a single injection of SD/01. Data from these normal volunteers also indicate that mobilization of CD34 + cells and progenitors may occur in a more timely manner and to around the same absolute numbers as with repeated daily injections of unmodified Filgrastim. These data indicate that SD/01 represents an efficacious novel form of Filgrastim with actions sustained for between one and two weeks from a single injection.

Protein Turnover, Energy Expenditure and Body Composition in Patients with Acute Leukaemia Undergoing Chemotherapy

1. Measurements of whole body protein turnover using the (13)C-leucine tracer technique, of body composition using anthropometric measurements and DEXA scanning, and of resting energy expenditure (REE) assessed by indirect calorimetry were made in 8 patients with acute leukaemia undergoing a single course of chemotherapy. Measurements were made in the post absorptive state immediately before chemotherapy and were repeated close to the time of discharge from hospital (mean days in hospital 31 ± 4.3, range 22-35), a mean of 23 ± 4.8 days after completion of chemotherapy. 2. The mean weight loss was 3.63kg (P < 0.001) with significant reductions in the mean non dominant mid arm circumference (1.29cm, P < 0.01), biceps (0.7mm, P < 0.01) and triceps (1.9mm, P < 0.05) skinfold thicknesses. DEXA scanning showed a reduction of mean body fat (1.22kg, P < 0.05) and lean tissue (1.85kg, P < 0.01). 3. There was a reduction in whole body leucine flux (Q) by 35% (P < 0.01) and synthesis (S) by 40% (P < 0.001) with no change in catabolism (C) over the course of admission. 4. There were no significant changes in REE.

Idarubicin in combination with cytarabine and VP-16 in the treatment of post myelodysplastic syndrome acute myeloblastic leukemia (MDS-AML).

Fifteen patients with a primary myelodysplastic syndrome (MDS) transformed into acute myeloblastic leukemia (AML) were treated with an intensive chemotherapy regimen containing idarubicin. A complete response (CR) was obtained in 10 patients (66.6%). In five of them this was achieved after a single course of chemotherapy. The median time to achieve a CR was 32 days (range 16-42). A partial remission (PR) was obtained in 2 patients after two induction courses of chemotherapy. One patient died during the first induction course following acute respiratory distress syndrome (ARDS) complication, whereas the chemotherapy regimen failed in 2 patients. A short interval between MDS and transformation into AML was associated with a better chance of achieving a CR. Age, karyotype, type of MDS, peripheral blood or bone marrow findings appeared to have no influence on the response to treatment. The median event free survival for patients who achieved CR was 15 months and the median actuarial survival 18 months. These preliminary results need to be confirmed in a multicentre prospective study comparing idarubicin with other anthracyclines.

Stem cell apheresis in patients with acute nonlymphocytic leukemia

In patients with acute nonlymphocytic leukemia (ANLL) it has previously been reported that the number of blood-derived hemopoietic stem cells (HSC) is very low during the remission phase. 1,2 However, we and others have recently demonstrated that the concentration of granulocyte-macrophage precursors (CFU-GM cells) in the peripheral blood could be increased to 10- to 40-fold above the mean value in normal subjects during the period of marrow reconstitution following aplasia (or hypoplasia) induced by previous chemotherapy. 1,3 To collect high numbers of circulating HSC, leukocyta-phereses could be performed during this short period of “recirculation” of blood-derived progenitors. However, patients with ANLL may be subjected to different chemotherapy regimens that vary according to the age of the patients, the status of the leukemia, and the therapeutic strategy. The amplitude of the recirculation of CFU-GM cells during remission is influenced mostly by the type of chemotherapy administered to the patient. 1 In order to evaluate this phenomenon, we serially assayed peripheral blood CFU-CM cells in 26 ANLL patients. The mean value of the highest recorded peak (HRP) level was 4370 CFU-GM/mL (1133 to 9066) in 13 patients who achieved complete remission after a single course of induction treatment including cytosine arabinoside (Ara-c) (100 mg/m2 × 10 days) and daunorubicin (DNR) (60 mg/m2 × 3 days). As mentioned in a previous report, HPR levels of CFU-GM cells observed in two patients given a late, intensification treatment (with DNR: 300 mg/m2) were similar to those observed in these latter 13 patients. 1 The recirculation of CFU-GM cells was less marked in seven patients who received two consecutive courses of induction chemotherapy or in four other patients receiving less intensive treatment as consolidation. 1,2 These results confirm the results of our previous report and the data reported by To et al., who studied 13 ANLL patients during the very early remission phase following induction chemotherapy. 3 They found that the mean value of the HRP level of CFU-GM cells was 2796/mL (370 to 14520) and concluded that the early remission period after one single course of chemotherapy could be the best time for collection of circulating HSC in ANLL patients.