Effectiveness and Tolerance of Azacitidine for Treating Patients with Chronic Myelomonocytic Leukemia in Community-Based Management.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4855-4855
Author(s):  
Regina Garcia ◽  
Maria E Amutio ◽  
Manuel Almagro ◽  
Alicia Bailen ◽  
Jose F Falantes ◽  
...  
Keyword(s):  
Adverse Events ◽  
Injection Site Reaction ◽  
Chronic Myelomonocytic Leukemia ◽  
Phase Iii ◽  
World Health ◽  
Compassionate Use ◽  
Community Based ◽  
Dosing Schedule ◽  
Grade 3 ◽  
Myelomonocytic Leukemia

Abstract Abstract 4855 Introduction Azacitidine (AZA) was recently approved in Europe by the EMEA for the treatment of Chronic Myelomonocytic Leukemia (CMMoL). Traditionally, CMMoL has been considered as part of the myelodysplastic syndrome (MDS) according to the FAB (French-American-British) classification. Nowadays, according to the criteria proposed by the World Health Organization (WHO), it is included as a subgroup of diseases of mixed characteristics named as myelodysplastic/myeloproliferative diseases (MDS/MPD) separate from MDS. Recent discoveries in the molecular biology of CMMoL have provided new therapeutic agents to test. Treatment with AZA was approved by the EMEA on the basis of the AZA-001 phase III clinical trial. AZA is also approved for the treatment of the MDS. AZA was available in Spain under compassionate use before its regulatory approval (May 2009). We present the effectiveness and tolerance data for AZA clinical activity in patients with CMMoL included in the Spanish compassionate use registry. Material and Methods We present the preliminary clinical results taken from data from a longitudinal, multicenter Spanish patient registry, which retrospectively collected data from community-based hematology clinics on the disease course and management of patients with CMMoL treated in a compassionate use setting with AZA, in whom the dosing schedule administered was documented. AZA dosing was applied to the patients in two different dosing schedules in 28-day cycles: either days 1, 2, 3, 4 and 5 or days 1, 2, 3, 4, 5, 8 and 9. Choice of schedule was based on patient status. As of August 1, 2009, data from 10 patients with MDS diagnosed according to the WHO criteria had been collected. Response to treatment was assessed using the International Working Group (IWG 2006) criteria. Treatment toxicity was assessed using the NCI-CTCAE version 3.0 criteria. Results Data collection comprised results from 8 male and 2 female, with a median age of 64 years (range 62-80). An intermediate-2/high IPSS risk was documented in 20% of the patients and a 0-1 ECOG status before treatment initiation was documented 80% of the patients. Patients received a median of 5 cycles of AZA (range 2-12). The most frequently used dose was 75 mg/m2 (90%). A 5-day dosing schedule was administered to 70% of the patients and a 5+2 day dosing schedule with 2 free days was administered to the remaining 30%. The most frequent administration route was subcutaneous injection (70%). According to the IWG 2006 response criteria, 20% of patients obtained a complete response, 20% achieved a complete bone marrow response, and, in a further 10%, hematological response was documented. The grade 3-4 adverse events, regardless of their relationship with the active treatment, were of hematological nature (neutropenia n=5, thrombocytopenia n=4, anemia n=1). Other grade 3-4 adverse events documented were rash (n=2), injection site reaction (n=1), hypotension (n=1) and constitutional symptoms (n=1). These rates do not differ from those obtained in the AZA-001 study. Conclusions These results demonstrate that AZA is effective for the treatment of patients with CMMoL in community-based management. Different dosing schedules are prescribed to patients with CMMoL treated with AZA in the community-based setting. Further analyses from this registry are awaited. Disclosures No relevant conflicts of interest to declare.

scholarly journals Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

2011 ◽  
Vol 29 (18) ◽  
pp. 2521-2527 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Steven D. Gore ◽  
Christopher Cogle ◽  
Renee Ward ◽  
Tao Shi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Chronic Myelomonocytic Leukemia ◽  
Maximum Effect ◽  
Clinical Activity ◽  
Grade 3 ◽  
Myelomonocytic Leukemia ◽  
Acute Myeloid

Purpose To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and Methods Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral azacitidine. Results Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. Conclusion Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.

558 Programmed death (PD)-1 and PD-ligand-1 inhibitors in the treatment of non-small cell lung cancer: a systematic review of their efficacy and safety

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A592-A592
Author(s):  
Melissa Lingohr-Smith ◽  
Chelsea Deitelzweig ◽  
Grace Lin ◽  
Jay Lin
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Patient Outcomes ◽  
Nsclc Patient ◽  
Response Rates ◽  
Phase Iii ◽  
Combination Therapies ◽  
Phase Iii Clinical Trials ◽  
Programmed Death ◽  
Grade 3

BackgroundTreatment advances have been made in non-small cell lung cancer (NSCLC) with the development and approval of programmed death (PD)-1 and PD-ligand 1 (PD-L1) inhibitors. PD-1 and PD-L1 inhibitors may be used as monotherapies or in combination with other agents and have been shown to improve NSCLC patient outcomes in clinical trials. We conducted a systematic search to compare the efficacy and safety of PD-1/PD-L1 inhibitors in the treatment of NSCLC.MethodsA systematic literature search of PubMed was conducted to identify phase III clinical trials in which the efficacy of PD-1/PD-L1 inhibitors in the treatment of NSCLC was evaluated. PD-1 inhibitors included nivolumab and pembrolizumab; PD-L1 inhibitors included atezolizumab, avelumab, and durvalumab. Patient characteristics and efficacy data were extracted.ResultsSixteen phase III clinical trials were identified (nivolumab=4; pembrolizumab=5; atezolizumab=5; avelumab=1; durvalumab=1). Across the 3 nivolumab monotherapy trials (n=638; median ages: 61–63 years), median progression-free survival (PFS) ranged 2.3–4.2 months; response rates ranged 19%-26%; grade 3/4 adverse events occurred in 7%-18% of patients. Nivolumab in combination with iplimumab (n=583; median age: 64 years) had a median PFS of 5.1 months and response rate of 33%; grade 3/4 adverse events occurred in 33% of patients. Across the 3 pembrolizumab monotherapy trials (n=1,481; median ages: 63–64 years), median PFS ranged 3.9–10.3 months; response rates ranged 18%-45%; grade ≥3 adverse events occurred in 13%-27% of patients. In the 2 pembrolizumab combination therapy trials (n=688; median ages: 65 years), median PFS ranged 6.4–8.8 months; response rates ranged 48%-58%; grade ≥3 adverse events occurred in 67%-70% of patients. In the 4 atezolizumab combination therapy trials (n=1,486; median ages: 63–64 years), median PFS ranged 6.3–8.3 months; response rates ranged 47%-63.5%; grade 3/4 adverse events occurred in 54%-73% of patients. In the 3 monotherapy trials of atezolizumab (n=613; median age: 63 years), avelumab (n=396; median age: 64 years), and durvalumab (n=476; median age: 64 years), the median months of PFS were 2.7, 2.8, and 17.2, respectively; response rates were 14%, 15%, and 30%, respectively; grade ≥3 adverse events occurred in 15%, 10%, and 30.5% of patients, respectively.ConclusionsAlthough treatment responses varied, most of the evaluated PD-1/PD-L1 inhibitors were associated with a clinical benefit for NSCLC trial patients. Generally, treatment efficacy was greater with combination therapies, but adverse events occurred more frequently. Innovations in the targeting/personalization of PD-1/PD-L1 combination therapies will likely lead to improved NSCLC patient outcomes and further research is needed in this regard.

scholarly journals Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 901-901
Author(s):  
Sara Bringhen ◽  
Massimo Offidani ◽  
Pellegrino Musto ◽  
Anna Marina Liberati ◽  
Giulia Benevolo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Community Based ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Grade 3 ◽  
To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in >75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p<0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

Myelodysplastic/Myeloproliferative Neoplasms

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 264-272 ◽  
Author(s):  
Mario Cazzola ◽  
Luca Malcovati ◽  
Rosangela Invernizzi
Keyword(s):  
Clinical Laboratory ◽  
Myeloproliferative Neoplasms ◽  
Chronic Myelomonocytic Leukemia ◽  
World Health ◽  
Refractory Anemia ◽  
Molecular Diagnostic ◽  
Juvenile Myelomonocytic Leukemia ◽  
Lymphoid Tissues ◽  
Ring Sideroblasts ◽  
Myelomonocytic Leukemia

Abstract According to the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, myelodysplastic/myeloproliferative neoplasms are clonal myeloid neoplasms that have some clinical, laboratory, or morphologic findings that support a diagnosis of myelodysplastic syndrome, and other findings that are more consistent with myeloproliferative neoplasms. These disorders include chronic myelomonocytic leukemia, atypical chronic myeloid leukemia (BCR-ABL1 negative), juvenile myelomonocytic leukemia, and myelodysplastic/myeloproliferative neoplasms, unclassifiable. The best characterized of these latter unclassifiable conditions is the provisional entity defined as refractory anemia with ring sideroblasts associated with marked thrombocytosis. This article focuses on myelodysplastic/myeloproliferative neoplasms of adulthood, with particular emphasis on chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts associated with marked thrombocytosis. Recent studies have partly clarified the molecular basis of these disorders, laying the groundwork for the development of molecular diagnostic and prognostic tools. It is hoped that these advances will soon translate into improved therapeutic approaches.

scholarly journals Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report

2019 ◽  
Vol 54 (6) ◽  
pp. 1901522 ◽  
Author(s):  
Sergey Borisov ◽  
Edvardas Danila ◽  
Andrei Maryandyshev ◽  
Margareth Dalcolmo ◽  
Skaidrius Miliauskas ◽  
...  
Keyword(s):  
Adverse Events ◽  
Active Drug ◽  
Clinical Information ◽  
World Health ◽  
Drug Resistant ◽  
Serious Adverse Events ◽  
Resistant Tuberculosis ◽  
Drug Safety Monitoring ◽  
Grade 3 ◽  
Health Organization

The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1–2) and 57 (11.3%) as serious (grade 3–5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.

Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy.

1997 ◽  
Vol 15 (1) ◽  
pp. 251-260 ◽  
Author(s):  
P Rougier ◽  
R Bugat ◽  
J Y Douillard ◽  
S Culine ◽  
E Suc ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Metastatic Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Objective Response ◽  
World Health ◽  
Who Grade ◽  
Pretreated Patients ◽  
Grade 3

PURPOSE To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients. PATIENTS AND METHODS Two hundred thirteen patients (aged 18 to 75 years) with metastatic colorectal cancer, World Health Organization (WHO) performance status < or = 2, and life expectancy > or = 3 months were treated with CPT-11 350 mg/m2 every 3 weeks. All 178 patients eligible for efficacy analysis had not received more than one prior fluorouracil (5-FU)-based chemotherapy regimen (adjuvant or palliative) and had adequate hematologic, renal, and hepatic function. RESULTS Primary tumor sites were the colon (71%) and rectum (28%). Sixty-six percent of the patients had > or = two metastatic sites. Ninety-eight percent of the patients had undergone previous surgery, and 77.5% had received prior chemotherapy. Thirty-two of 178 eligible patients achieved on objective response (four complete responses [CRs] and 28 partial responses [PRs]; response rate, 18%; 95% confidence interval, 12.6% to 24.4%), 65 were stable, and 59 progressed. The response rate was 17.7% in the pretreated group and 18.8% in the chemotherapy-naive group. Within the former subgroup, response rates of 16.1% were reported in patients who were progressive on prior 5-FU chemotherapy and 19.1% in patients who were progressive off such treatment. The median duration of objective response (9.1 months) and median time to achievement of a response (9.3 weeks) did not differ between chemotherapy-naive and pretreated patients. The most frequent adverse events were neutropenia, which developed in 80% of the patients, delayed diarrhea (87%), alopecia (88%), fatigue (81%), and nausea/vomiting (77%). All these adverse events were manageable. Severe (WHO grade 3 or 4) neutropenia was only observed in 18% of the cycles, leukopenia in 11%, delayed diarrhea in 11%, and nausea and vomiting in 3%. Development of simultaneous grade 3 or 4 neutropenia and delayed diarrhea during 4% of the cycles was the safety issue of greatest concern. CONCLUSION CPT-11 has definite activity in the treatment of advanced metastatic colorectal cancer both in chemotherapy-naive and in pretreated patients who experienced disease progression on 5-FU, which suggests a lack of cross-resistance between CPT-11 and 5-FU. Diarrhea and neutropenia, the major toxicities of CPT-11, contribute to the risk to develop febrile neutropenic sepsis.

Ecteinascidin-743: A Marine-Derived Compound in Advanced, Pretreated Sarcoma Patients—Preliminary Evidence of Activity

2001 ◽  
Vol 19 (5) ◽  
pp. 1248-1255 ◽  
Author(s):  
S. Delaloge ◽  
A. Yovine ◽  
A. Taamma ◽  
M. Riofrio ◽  
E. Brain ◽  
...  
Keyword(s):  
Phase I ◽  
Performance Status ◽  
Bone Sarcoma ◽  
Maximum Tolerated Dose ◽  
World Health ◽  
Compassionate Use ◽  
Bulky Disease ◽  
Clinical Resistance ◽  
Ecteinascidin 743 ◽  
Grade 3

PURPOSE: To report the activity of the chemotherapeutic agent ecteinascidin-743 (ET-743) in advanced pretreated sarcoma patients observed during a phase I study and a named-patient basis, compassionate use program. PATIENTS AND METHODS: Twenty-nine pretreated, advanced soft tissue sarcoma (STS) and bone sarcoma patients consecutively seen in our centers were included, 12 from a phase I trial and 17 from a compassionate use program cohort. Patients were treated every 3 weeks at either 1,200 μg/m2 (six patients), 1,500 μg/m2 (the recommended dose, 22 patients), or 1,800 μg/m2 (the maximum-tolerated dose, one patient), given as a 24-hour infusion every 3 to 4 weeks. RESULTS: Fifteen men and 14 women were treated. The median patient age was 46 years (range, 16 to 71 years), with a median World Health Organization performance status of 1 (range, 0 to 2). Twenty-five patients had STS, three had osteosarcoma, and one had Ewing’s sarcoma, and all had progressive disease at accrual. Fifteen patients had bulky disease, and 14 had clinical resistance to anthracyclines. A total of 136 treatment cycles were administered (median per patient, five cycles; range, one to 12 cycles). Transient grade 3 and 4 transaminitis was reported in 24% and 5% of cycles, respectively, grade 3 to 4 neutropenia occurred in 32% of cycles, with concomitant sporadic grade 3 to 4 thrombocytopenia in 5.1% of cycles. Grade 2 to 3 asthenia occurred in 21% of cycles. There were two partial responses (PRs) in STS patients and two PRs in osteosarcoma patients. Two minor responses and 10 disease stabilizations were seen. Median duration of response was 10.5 months (range, 2.8 to 15 months), and mean duration of stabilization was 5.2 months. CONCLUSION: ET-743 has activity in advanced, highly pretreated STS and osteosarcoma patients and warrants further trials to establish the extent of its activity in this setting.

Study of Intra-Venous Homoharringtonine (HHT) in the Treatment of Myelodysplastic Syndrome (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4903-4903
Author(s):  
Gautam Borthakur ◽  
Hagop Kantarjian ◽  
Elihu Estey ◽  
Srdan Verstovsek ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Phase Ii Study ◽  
Chronic Myelomonocytic Leukemia ◽  
Refractory Anemia ◽  
Intracranial Bleed ◽  
Fever Treatment ◽  
Grade 3 ◽  
Secondary Mds ◽  
Myelomonocytic Leukemia ◽  
Modest Activity

Abstract Homoharringtonine (HHT) is a plant alkaloid that inhibits protein synthesis, induces differentiation and apoptosis of myeloid cells. We initiated a phase II study of intra-venous HHT in patients (pts) diagnosed with MDS by WHO criteria to assess safety and efficacy of HHT in this setting. Responses were recorded according to the MDS response criteria defined by NCI working group. Pts received HHT 2.5 mg/m2 by continuous 24-hour intravenous infusion daily for 7 days every 4 weeks until a) a complete remission (CR) was achieved, or b) failure to achieve a CR after 3 courses of therapy or c) unacceptable toxicities developed. The dose was increased to 3.0 mg/m2 for pts with no response after the 1st course. Nine pts have been enrolled (6 male and 3 female). Median age was 70 yrs (range 55 to 84 yrs) and 4 pts had secondary MDS. Four pts had refractory anemia with excess blasts-1 (RAEB-1), 3 had RAEB-2, 1 had chronic myelomonocytic leukemia (CMML-1) and 1 had MDS/myeloproliferative disorder (MDS/MPD). IPSS score was intermediate-1 in 1 pt, intermediate-2 in 7 pts and high in 1 pt. Seven pts (78%) received only one cycle of HHT. One (11%) pt had a CR (including cytogenetic CR) that lasted for 67 days, 5 pts discontinued treatment due to lack of response and1 pt with stable disease decided to withdraw from the study. After a median follow-up of 54 days (range, 37 to 145 days) 2 pts have died, one on day 37 due to intracranial bleed secondary to thrombocytopenia and one on day 39 due to invasive fungal infection. Grade 2 toxicities included fatigue (4 pts), diarrhea (3 pts) and nausea (3 pts). Grade 3 cytopenias were seen in all pts and grade 3 nausea in 1 pt. Three pts had neutropenic fever. Treatment during first course was interrupted after 5 days of infusion in 1 pt due to grade 3 congestive heart failure (CHF). This pt received his second course of treatment without recurrence of CHF. In conclusion, HHT has modest activity in intermediate to high risk MDS. After first interim analysis, the study meets criteria for continued accrual.

A Prospective, Randomized, Phase III Study of Melphalan 200 mg/m2 (MEL200) Versus Melphalan 100 mg/m2 (MEL100) in Newly Diagnosed Myeloma Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 55-55 ◽  
Author(s):  
Antonio Palumbo ◽  
Sara Bringhen ◽  
Maria Teresa Petrucci ◽  
Antonietta Falcone ◽  
Anna Marina Liberati ◽  
...  
Keyword(s):  
Stem Cell ◽  
Adverse Events ◽  
Response Rate ◽  
Complete Response Rate ◽  
Complete Response ◽  
Phase Iii ◽  
Psychiatric Disease ◽  
High Dose ◽  
Free Survival ◽  
Grade 3

Abstract Several trials have shown the superior impact of high-dose melphalan (usually 200 mg/m2, MEL200) versus standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m2, MEL100) was also superior to the standard dose, but MEL100 has not been clinically compared with MEL200 in a randomized study. In a case-matched study, response rate and event-free survival of MEL200 were superior to MEL100, but overall survival (OS) was similar. In this prospective, randomized, phase III trial, we compared the efficacy and toxicity of MEL200 and MEL100. Between January 2002 and July 2006, 299 patients were enrolled. Inclusion criteria were previously untreated myeloma, aged < 65 and Durie and Salmon stage II or III. Exclusion criteria were abnormal cardiac function, respiratory disease, abnormal liver function, abnormal renal function, HBV, HCV, or HIV positivity, concomitant cancer or psychiatric disease. The institutional review board approved the protocol and written informed consent was obtained from all patients. All patients received: 2 dexamethasone-doxorubicin-vincristine debulking courses (doxorubicin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1, 2, 3, 4, each course repeated every 28 days), 2 cycles of cyclophosphamide (4 g/m2, day 1) plus G-CSF followed by stem cell harvest. The MEL200 group was conditioned with 2 cycles of melphalan 200 mg/m2 followed by stem cell reinfusion; the MEL100 group was conditioned with 2 courses of melphalan 100 mg/m2 followed by stem cell reinfusion. At the present, 246 patients, median age 57 (range 32–65), completed the assigned therapy and were evaluated for response, progression-free survival (PFS) and OS. One-hundred and twenty-four patients were randomized to MEL200 and 122 to MEL100. Patient characteristics were similar in both groups. Abnormal cytogenetics (13q deletion, t(4;14), t(11;14), p53) were 75% in MEL200 patients and 56% in MEL100 patients (p=0.05). Forty-six patients did not complete tandem MEL200; 36 patients did not complete tandem MEL100. The near complete response rate of MEL200 was superior to MEL100 (32% versus 18%, p=0.011), but partial response was 80% versus 71%, respectively (p=0.079). The median follow-up for censored patients was 26.5 months. The 3 years PFS was 51% in the MEL200 arm and 33% in the MEL100 arm (HR=0.81, 95% CI 0.55–1.21, p=0.31). The 3 years OS was 86% in the MEL200 group and 71% in the MEL100 group (HR=0.82, 95 CI 0.45–1.48, p=0.51). Duration of grade 4 neutropenia and thrombocytopenia was comparable in two arms, but MEL200 patients required more platelet transfusions (p=0.03). Grade 3–4 non-hematological adverse events were reported in 49% of the MEL200 patients and in 38% of the MEL100 patients (P=0.07). The most frequent grade 3–4 adverse events were infections (54% of MEL200 patients versus 45% of MEL100 patients, p=0.25), mucositis (31% of MEL200 patients versus 7% of MEL100 patients, p=0.002) and gastrointestinal toxicities (20% of MEL200 patients versus 14% of MEL100 patients, p=0.3). In conclusion, MEL200 resulted in a significantly higher near complete response rate but this did not translate in a superior PFS and OS.

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