Incidence Of Toxic Death Research Articles

Comorbidities Reduce Response to Induction Treatment and Survival in Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia

Background. Comorbidities have a well-established prognostic value in the majority of hematologic neoplasms. However, the impact of comorbidities on adult patients with acute lymphoblastic leukemia (ALL) has been poorly investigated to date. Aims. In this retrospective study of a monocentric cohort of 112 adults with Philadelphia-negative (Ph-neg) ALL consecutively diagnosed between 1990 and 2018 we aimed to assess the association between comorbidities at diagnosis and remission rate, the frequency and severity of adverse events (AE) during frontline treatment, and long-term outcome. Patients and methods. Patients were included, regardless of age, if treated within or according to clinical protocols aimed at curing. Patients initially treated with low-intensity/palliative care were not considered. Ph-positive patients were excluded, as their treatment modalities markedly changed over years due to the availability of tyrosine kinase inhibitors. Patients were defined as high risk if one or more of the following features were present: WBC >30x109/L for B-cell precursor (BCP) or >100x109/L for T-cell precursor (TCP), pro-B, early or mature T ALL phenotype, high risk cytogenetics (according to the ESMO 2016 guidelines), or central nervous system involvement. Comorbidities recorded at diagnosis were classified according to the Charlson Comorbidity Index (CCI). Classification and grading of AE was performed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Responses were defined according to the ESMO 2016 guidelines. Minimal residual disease (MRD) was assessed by 6- or 8-colour flow cytometry with a 10-4 sensitivity. Variables tested for association with complete remission (CR) and MRD-negative status were: age group (stratified into quartiles), gender, phenotype (BCP or TCP), WBC, karyotype, risk class, and CCI score. Event-free survival (EFS) was calculated from the first CR to relapse or death. Overall survival (OS) was calculated from diagnosis until death. EFS and OS were estimated using the Kaplan-Meier method. Results. Median age at diagnosis was 43 years (range 14-75). BCP and TCP were 78% and 22%, respectively. Overall, 51 patients (46%) were considered as standard risk, 46 (41%) as high risk, and 15 (13%) were unclassifiable due to the lack of cytogenetics. CCI score distribution was as follows: 0 (n=66; 59%), 1 (n=18; 16%), 2 (n=9; 8%), and ≥3 (n=19; 17%). CR after induction therapy was obtained by 95/112 patients (85%). CCI was the only variable significantly associated to CR achievement (0-1 vs ≥2: 91% vs 68%; p=0.012). MRD status at the end of induction was evaluable in 64 out of 95 patients in CR and was negative in 28 (44%). No pretreatment variable predicted for the achievement of MRD complete response. Eight patients (7%) died before the first response evaluation; early death rate was significantly higher in patients with CCI ≥2 than in patients with CCI 0-1 (21% vs 2%; p=0.003). Conversely no differences in AE frequency and severity were observed according to CCI (p=0.847) or age group (p=0.881). After a median follow-up of 35 months, 46 patients (41%) were alive. OS was significantly longer in patients with CCI 0-1 as compared to CCI ≥2 (median 87 months, 95%CI: 31 to not reached vs 13 months, 95%CI: 5-36; p<0.001). Notably, pre-treatment risk stratification lost prognostic value in predicting OS and EFS in CCI 0-1 patients, while in CCI ≥2 patients retained its significance (Figure). Overall, 58 patients (52%) were primary refractory or relapsed. Relapse rate was similar according to age groups, phenotype, risk class, and CCI score. CR rate after salvage treatment (CR2) was higher in younger patients (≤43 vs >43 years: 81% vs 44%; p=0.014) and tended to be higher in patients treated with blinatumomab or inotuzumab rather than with standard chemotherapy (82% vs 55%, p=0.17). While there were no differences in CR2 according to CCI group, median survival after first relapse was 12.1 months (95%CI: 7.83-15.24) for CCI 0-1 vs 6.92 months (95%CI: 2.49-12.59) for CCI≥2(p=0.021). Conclusions. Comorbidities have a significant prognostic impact in intensively-treated adults with Ph-neg ALL. Patients with low comorbidities (CCI 0-1) had superior CR rates and less incidence of toxic death after induction, and pre-treatment high risk features did not have a detrimental impact in this group. Figure Disclosures Krampera: Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Bonifacio:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria.

Phase 1, multicenter, open-label, dose-escalation, combination study (NCT02103335) of pomalidomide (POM), marizomib (MRZ, NPI-0052), and dexamethasone (DEX) in patients with relapsed and refractory multiple myeloma (MM); study NPI-0052-107 preliminary results

toxic deaths. Methods: 1173 newly diagnosed MM patients entered the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) and European Myeloma Network (EMN) trials from May 2006 to September 2012. Overall, 511 patients received bortezomiband 662 patients lenalidomide-containing regimens. Results: 1146 patients started therapy and could be evaluated for this analysis. Death within 24 months of start of therapy occurred in 207 patients (18%). Among them, 61 patients (5%) died due to adverse events. Toxic deaths within 60 days occurred in 12 patients (1%) with a linear increase over time of 1% every 6 months. Thirty percent of deaths were attributable to cardiac complications (18 pts), 28% to infections (17 pts) and 15% to vascular complications (9 pts). There was no difference in the incidence of toxic deaths between patients receiving bortezomib (31 pts, 6%) or lenalidomide-containing regimens (30 pts, 5%, p1⁄40.32), nor in the proportions of toxic events. The incidence of toxic deaths was significantly higher in patients older than 80 years (11/107 [10%], p1⁄40.005). In multivariate analysis, factors associated with increased risk of early mortality were age (HR 1.09 per 1 year increase, p1⁄40.002) and ISS stage (HR 3.81, p1⁄40.01 ISS 2 vs ISS 1; HR 5.69, p1⁄40.002 ISS 3 vs ISS 1). Poor performance status was not a predictor of early death (HR 1.25, p1⁄40.59). By analyzing the impact of response, toxic deaths within 6 months occurred in patients with a suboptimal response (overall response rate 29%). Conclusions: Novel agents have substantially reduced the risk of toxic deaths as compared to conventional therapy. Nevertheless one-third of early deaths occurred due to cumulative specific drug-related toxicities. Cardio-vascular events and infections are the main causes. Greater tumor burden and activity (defined by ISS stage) increased the risk of death. The 2-fold higher risk of toxic mortality in octogenarians indicates the need for a careful assessment of frailty to identify patients who may benefit from a gentler approach.

The Genomic and Transcriptional Landscape of Waldenström’s Macroglobulinemia Impacts Disease Presentation, Overall Survival, and Therapeutic Response

toxic deaths. Methods: 1173 newly diagnosed MM patients entered the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) and European Myeloma Network (EMN) trials from May 2006 to September 2012. Overall, 511 patients received bortezomiband 662 patients lenalidomide-containing regimens. Results: 1146 patients started therapy and could be evaluated for this analysis. Death within 24 months of start of therapy occurred in 207 patients (18%). Among them, 61 patients (5%) died due to adverse events. Toxic deaths within 60 days occurred in 12 patients (1%) with a linear increase over time of 1% every 6 months. Thirty percent of deaths were attributable to cardiac complications (18 pts), 28% to infections (17 pts) and 15% to vascular complications (9 pts). There was no difference in the incidence of toxic deaths between patients receiving bortezomib (31 pts, 6%) or lenalidomide-containing regimens (30 pts, 5%, p1⁄40.32), nor in the proportions of toxic events. The incidence of toxic deaths was significantly higher in patients older than 80 years (11/107 [10%], p1⁄40.005). In multivariate analysis, factors associated with increased risk of early mortality were age (HR 1.09 per 1 year increase, p1⁄40.002) and ISS stage (HR 3.81, p1⁄40.01 ISS 2 vs ISS 1; HR 5.69, p1⁄40.002 ISS 3 vs ISS 1). Poor performance status was not a predictor of early death (HR 1.25, p1⁄40.59). By analyzing the impact of response, toxic deaths within 6 months occurred in patients with a suboptimal response (overall response rate 29%). Conclusions: Novel agents have substantially reduced the risk of toxic deaths as compared to conventional therapy. Nevertheless one-third of early deaths occurred due to cumulative specific drug-related toxicities. Cardio-vascular events and infections are the main causes. Greater tumor burden and activity (defined by ISS stage) increased the risk of death. The 2-fold higher risk of toxic mortality in octogenarians indicates the need for a careful assessment of frailty to identify patients who may benefit from a gentler approach.

Development of treatment and clinical results in childhood acute myeloid leukemia in the Czech Republic

Treatment of childhood acute myeloid leukemia (AML) was unified in the year 1993 according to acute myeloid leukemia-Berlin–Frankfurt–Munster (AML-BFM) protocols in the Czech Republic. We evaluated data on clinical and therapeutic results in children with AML treated in three subsequent trials, comparing two periods, June 1993 to February 2004 (AML-BFM 93 and 98) vs. March 2004 to December 2009 (AML-BFM 2004 trial). Data of 182 eligible patients were analyzed, 125 in AML-BFM 93 and 98 trials, and 57 in AML-BFM 2004 trial enrolled prior to December 2009. Down syndrome patients were excluded from analysis. In studies AML-BFM 93 and 98, 79.2 % of 125 patients achieved complete remission (CR), 19 patients (15.2 %) suffered from early death, 7 (5.6 %) were nonresponders, 33 (33.3 %) relapsed, 12 (12.1 %) died in CR, and 2 patients (2.0 %) developed secondary malignancy. The estimated probability of event-free survival (pEFS) at 5 years was 41.6 %, the overall survival (OS) at 5 years was 46.4 %. In AML-BFM 2004 trial, 93 % of 57 patients attained CR, 3 patients (5.2 %) suffered from early death, 1 (1.8 %) was nonresponder, 16 (30.2 %) relapsed, 2 (3.8 %) died in CR, and 2 patients (3.5 %) developed secondary malignancy. The estimated pEFS at 5 years was 56.1 %, 5-years overall survival (5y-OS) was 73.7 %. Gradual improvement of CR rate and OS together with decreasing incidence of toxic deaths in AML patients were achieved because of gain of experience with very intensive modern treatment centralized in a limited number of institutions.

History of treatment and long-term outcome in children with acute lymphoblastic leukemia in the Czech Republic

PURPOSE: Treatment of childhood acute lymphoblastic leukemia (ALL) was unified in the year 1986 in the Czech Republic using BFM protocols. PATIENTS AND METHODS: Children were treated in 10 and later on in 8 centers localized at the pediatric departments of the biggest hospitals. More than 1.000 children and adolescents up to the age of 18 years were treated between 1986 and 2002 on three consecutive studies ALL-BFM 83, ALL-BFM 90 and ALL-BFM 95. RESULTS: Event-free survival and overall survival improved gradually from 58/62% on ALL-BFM 83 through 70.5/76.6% on ALL-BFM 90 until 72.1/80.2% on ALL-BFM 95. At the same time the incidence of toxic deaths was decreasing and the success in the achievement of complete remission was increasing. Diagnostics in the Czech Republic improved remarkably in the 1990 with gradual introduction of centralized flow cytometry and molecular genetic analysis in one reference laboratory (CLIP = Childhood Leukemia Investigation Prague), which since then has become an internationally respected research center. CONCLUSIONS: Building up a network of closely collaborating leukemia centers covering the whole country, together with the establishment of reference and research laboratories has paved the way for the implementation of the Czech Pediatric Hematology Working Group (CPH) into the international studies Interfant 99, EsPhALL and for the active role in ALL IC-BFM 2002, the I-BFM-SG international randomized trial for treatment of children and adolescents with non-B ALL starting in 2002.

Preliminary Results of the Addition of Rasburicase to the Reduction Cycle and Rituximab to the Induction and Consolidation Cycles of FAB Group C Chemotherapy in Children and Adolescents with Advanced Stage (Bone Marrow ±CNS) Mature B-Cell Non-Hodgkin Lymphoma (B-NHL): A Children's Oncology Group Report.

Abstract 104We previously demonstrated that children with mature B-NHL with advanced disease, CNS positive and/or Burkitt leukemia (B-ALL), have an 80% 5 yr EFS with FAB multiagent chemotherapy, however, an attempt to reduce cytotoxic chemotherapy (dose and duration) led to an inferior EFS (Cairo et al, Blood, 2007). The FAB group C therapy backbone is associated with substantial acute toxicity with > 50% incidence of grade III/IV mucositis and infection during both induction cycles and a 5% incidence of toxic deaths during therapy. (Cairo et al, Blood, 2007). Furthermore, pts are at high risk of tumor lysis (TLS) (16%) and renal failure (10%) during initiation of low dose cytoxan/Oncovin/prednisone (COP) reduction therapy and allopurinol prophylaxis (Cairo et al, Blood, 2007). We previously demonstrated CD20, the receptor to the chimeric antibody rituximab, is expressed in over 98% of all children with mature B-NHL (Perkins/Cairo et al, Clin Adv Hem, 2003). In adults (30-60 yrs) and elderly adults (≥ 60 yrs) with DLBCL, the addition of rituximab to CHOP or CHOP like chemotherapy has significantly increased the EFS and OS (Pfreundschüh et al, Lancet Oncology, 2006 and Coiffier et al, NEJM, 2002, respectively). Furthermore, rasburicase is more effective than allopurinol in rapidly reducing hyperuricemia in children and adolescents at high risk of TLS. (Goldman/Cairo et al, Blood, 2001). We therefore hypothesized that the addition of rituximab (anti-CD20 antibody) to the FAB group C chemotherapy induction and consolidation backbone and the addition of rasburicase to reduction therapy in children and adolescents with newly diagnosed high-risk mature B-NHL would be safe and well tolerated. We now report the preliminary results of 42 eligible pts with group C (≥25% blasts in BM and/or CNS+) enrolled on COG ANHL01P1 through January 2009. Therapy consisted of FAB Group C1 therapy (adria 1 hr infusion) as we have previously described (Cairo et al, Blood, 2007) with the addition of rasburicase (0.2 mg/kg/dose), generously supplied by Sanofi-Aventis, during the COP reduction and rituximab 375 mg/m2/dose, generously supplied by Genentech, day -2 and day 0 in COPADM2 and day 0 in CYVE 1 + 2 (4 doses, subpilot) and day -2 and day 0 in COPADM 1 + 2 and day 0 in CYVE 1 + 2 (six doses, pilot), respectively. Toxicity was measured according to the NCI CTCAE 3.0. LTLS and CTLS were defined as per Cairo/Bishop classification (Cairo et al, BJH, 2004). Median age 9.5 yrs, M/F 4/1, Burkitt 82%, CNS+ 34%, Uric acid ' 8 mg/dl 45%, LDH ≥ 2 time upper institutional limits 86%. The addition of rituximab was safe and well tolerated with 237 infusions and only one reported grade III allergic reaction directly related to rituximab. Two toxic deaths (pulmonary aspergillosis unrelated to study drugs and grade V typhlitis during the second induction cycle) occurred among the first 25 group C patients and the study was temporally closed to accrual in October 2006. No further toxic deaths have been reported among an additional 17 eligible patients enrolled since August 2008. The incidence of grade III/IV mucositis during COPADM 1 + 2 was 30% and 23% (Adria 1 hr), respectively, compared to 68% and 52% in FABLMB96 (Adria 6 hr). Similarly, the incidence of grade III/IV neutropenia/infection during the same two courses was 62% and 51%, respectively, compared to 80% and 76% in FABLMB 96. With non-alkaline hydration and rasburicase, 94% pts had an improved estimated glomerular filtration rate (GFR) at day 7 of reduction. The initial mean GFR ± SD vs. end of COP were 108 ± 42 and 173 ± 64 ml/min/1.73m2, respectively (p < 0.05). In pts without TLS at presentation, 19% and 0% developed laboratory TLS and clinical TLS after rasburicase. There were no toxicities definitely or probably related to rasburicase therapy. Among the 42 eligible patients, one patient failed to obtain a CR and progressed on therapy. In summary, the addition of rasburicase to FAB COP reduction is well tolerated and demonstrates excellent control of tumor lysis and prevention of renal failure. Finally, the addition of Rituximab to FAB COPADM 1 + 2 and CYVE 1+2 is well tolerated and does not increase the rate of mucositis and infection during induction. Based on these results, a future randomized international study is being planned to determine if the addition of rituximab to the FAB chemotherapy backbone in children with advanced stage (BM±CNS) mature B-NHL will significantly increase EFS/OS. Disclosures:Goldman:Sanofi-Aventia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Rituximab in children. Cairo:Sanofi-Aventis; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Obesity Independently Predicts Event Free Survival (EFS) in Adults with BCR-ABL-Negative Acute Lymphoblastic Leukemia (ALL). A Retrospective Analysis of Two GIMEMA Studies.

Obesity predicted decreased EFS in pediatric ALL (ASH 2004, Abstract#992). Here we report the effect of obesity, defined as body mass index >30, in 906 adults enrolled in two GIMEMA trials. The first study (1996–2001) included 45 obese (9.5%) and 426 non-obese patients. Obese patients were older, received lower total doses of vincristine (VCR) and daunomicin (DNR) and had more hepatic and pulmonary toxicity during induction than not-obese patients; the incidence of toxic deaths and complete remissions (CR) were similar. By multivariate analysis, obesity, high WBC, age >30y and presence of BCR-ABL at diagnosis independently predicted EFS. Hazard ratios (HR) for any events were respectively 1.506 (1.059–2.142, p=0.0228), 1.002 (1.001–1.003, p=0.0022)), 1.015 (1.006–1.025, p=0.0014) and 1.8 (1.4–2.4, p<0.0001). The effect of obesity on EFS was present across all levels of WBC, but was observed prevalently in BCR-ABL-negative patients. 3y-EFS in obese vs non-obese patients was 22.9% vs 39.5% (p=0.0064) in BCR-ABL negative patients and not significantly different (14% vs 22%, p=0.77 n.s.) in BCR-ABL positive patients. These results were verified in the following study started in 2000, which included 50 obese (11%) and 385 non-obese patients. In this study, obese patients received 28% and 21% less than the planned doses of VCR and DNR respectively; also they were more likely than non-obese patients to be >30 y of age and BCR-ABL-positive. The incidence of toxicity, toxic deaths and CR were similar in obese and non-obese patients. In the BCR-ABL negative patients, obesity tended to predict EFS. 2y-EFS was 26.6% in the obese and 49.4% in the non-obese patients (p=0.067). By multivariate analysis HR for any events of obesity, WBC>50 and age>30 were respectively 1.53 (0.92–2.58, p=0.107), 1.64 (1.12–2.39, p=0.012) and 1.74 (1.19–2.54, p=0.004). In conclusion, obesity seems associated with a poorer EFS in patients with BCR-ABL negative ALL; this might be caused by the lower doses of chemotherapy obese patients receive. Studies aimed to clarify chemotherapy pharmacokinetics, toxicity and efficacy in obese patients are warranted.

EORTC Cancer in the Elderly Task Force guidelines for the use of colony-stimulating factors in elderly patients with cancer

Increasing age is not, in itself, a contraindication to cancer chemotherapy. Myelosuppression, however, a common adverse consequence of the administration of many standard-dose chemotherapy regimens to both young and elderly patients with cancer, increases with age. The risk of development of febrile neutropenia may contribute to a reluctance to administer chemotherapy in the elderly patient population. We conducted a detailed literature search (1992–2002) to derive evidence-based conclusions on the value of prophylactic colony-stimulating factor (CSF) administration in elderly patients receiving chemotherapy. Sufficient evidence allows us to affirm that prophylactic granulocyte colony-stimulating factor (G-CSF) reduces the incidence of chemotherapy-induced neutropenia, febrile neutropenia and infections in elderly patients receiving myelotoxic chemotherapy for non-Hodgkin's lymphoma (NHL), small-cell lung cancer (SCLC) or urothelial tumours. Lack of available trial data does not allow similar conclusions to be drawn for other cancers studied, but it is likely that similar benefits would accrue from the use of prophylactic G-CSF. There is insufficient evidence to extend this recommendation to include the use of granulocyte-macrophage colony-stimulating factor (GM-CSF). There are insufficient data available to allow the evaluation of the impact of prophylactic CSF on the incidence of toxic deaths in elderly patients with cancer and this is a crucial question for geriatric oncology practice. There is no evidence in elderly patients that the delivery of standard-dose chemotherapy on schedule improves efficacy measures. The data show that febrile neutropenic events are more likely to occur during the first and second cycles of chemotherapy, thus prophylactic measures should be considered early in the course of treatment. Furthermore, since systematic dose reduction can impact on outcome, primary prophylactic use of G-CSF for all elderly patients receiving curative myelotoxic chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like) is indicated and we suggest a risk-adapted strategy with primary prophylactic G-CSF administration in high-risk patients. Dose intensification, through dose interval reduction, facilitated by prophylactic G-CSF, improved survival in elderly patients with some specific diseases. There is a need for further well-designed studies to identify the elderly patients who will benefit most from prophylactic G-CSF. To achieve this, we strongly urge the design of and participation in further trials.

Squamous cell carcinoma of the anal canal

Purpose: To report the results of primary radiotherapy for treatment of anal canal carcinoma from the University of Florida series and review issues related to treatment of this disease. Methods and Materials: Forty-nine patients were treated with primary radiation therapy (RT) for cure. Patients had a minimum 2-year follow-up (median, 9.8 years). After 1990, patients with lesions of at least 3 cm also received chemotherapy with fluorouracil (1000 mg/m 2) plus cisplatin (100 mg/m 2) or mitomycin (10–15 mg/m 2) if medically fit ( n = 26). RT was delivered with a 4-field box technique to deliver 45 Gy in 25 fractions. The inguinal nodes were treated daily using electrons to supplement the dose in that region to a total dose of 45 Gy if clinically negative or about 60 Gy if involved. There were no planned breaks. A 10- to 15-Gy boost was delivered using interstitial iridium 192 implant ( n = 32), en face 60Co field ( n = 5), or external-beam photon fields ( n = 11). Results: Local control rates at 5 years were 100% for T1N0, 92% for T2N0 or N1, 75% for T3N0, 67% for T4N0, 88% for T4N pos or T anyN2–3, and 85% overall. With surgical salvage, ultimate local control rates were 100%, 100%, 81%, 100%, and 88%, respectively, with 92% overall. Cause-specific survival rates at 5 years were 100% for Stage I, 88% for Stage II, 100% for Stage IIIA, and 70% for Stage IIIB. Absolute survival rates at 5 years were 62%, 68%, 100%, and 70%. Sphincter preservation rates were 83%, 79%, 75%, and 100% by stage and 81% overall. There was an improvement in local control with the addition of chemotherapy in more advanced disease, but it was not significant. There was an increase in acute toxicity with the addition of chemotherapy (12% ≥ Grade 4) but not long-term toxicity. Late toxicity requiring colostomy occurred in 6% of patients and consisted of soft tissue necrosis. Conclusions: The majority of patients with anal canal carcinoma can be treated with curative intent using a sphincter-sparing approach of radiation with or without chemotherapy even with advanced disease. With the addition of chemotherapy to radiation, there is an increased risk of acute toxicity and about 1–2% incidence of toxic death. Smaller tumors (T1 and early T2) probably do not require the addition of chemotherapy.

Optimal use of docetaxel (Taxotere®)

The safety of docetaxel (Taxotere) has been evaluated in the safety overview population consisting of 1070 patients recruited to phase II trials. These patients received a total of 4989 cycles of therapy (median four cycles per patient). Since docetaxel is known to be metabolized in the liver, hepatic impairment was predicted to be a risk factor for increased toxicity and was studied prospectively, comparing the 42 patients in the overview population with moderate hepatic impairment with the 1028 patients with liver function within normal limits. Hepatic dysfunction was associated with an increase in the percentage of cycles of therapy during which febrile neutropenia occurred and the number of patients suffering documented infection and severe (grade 3/4) stomatitis. The incidence of toxic death was also increased in patients with moderate hepatic impairment. The severity of fluid retention, a cumulative toxicity of docetaxel, was found to be reduced, and its onset delayed, by prophylactic treatment with corticosteroids for 5 days, starting 1 day before docetaxel administration. Treatment with corticosteroids was also recommended to reduce the incidence and severity of hypersensitivity reactions and cutaneous toxicities. The most frequent severe non-haematological toxicity of docetaxel was asthenia. Other non-haematological toxicities were generally mild or moderate.

Treatment of high risk myelodysplastic syndromes with idarubicin and cytosine arabinoside supported by granulocyte-macrophage colony-stimulating factor (GM-CSF)

In this prospective study, patients with ‘high risk’ primary MDS, namely RAEB or RAEBt, were treated with combination chemotherapy (CT) supported by GM-CSF. The induction CT consisted of idarubicin 6 mg/m 2 days 1–3 and cytosine-arabinoside 200 mg/m 2 in 12 h infusion, days 1–5. The GM-CSF 3 μg/kg s.c. was given on day 6 until the neutrophil count was 1 × 10 9/l. Postremission CT consisted of two similar courses. Patients not in remission after two courses of CT were considered as treatment failures. Twenty-two patients with a median age of 64 years, range 50–79 years (11 RAEB and 11 RAEBt) were evaluable. Twelve out of 22 patients (54.5%) achieved complete remission (CR) and four, partial remission. Six patients were resistant to treatment; there were two toxic deaths; seven patients achieved CR after the first course and five after two courses. The median time of neutrophil recovery to 1 × 10 9/l was day 15 (range 3–22) after the first course of treatment and day 14 (range 4–21) after the second. Thirteen out of 22 patients developed febrile episodes after the first course of treatment and nine after the second. The median duration of CR was 12 months. The median survival for CR patients was 24 months, for non-CR patients, 12 months; while survival for the whole population was 18 months. In conclusion, the results of this study indicate that the administration of moderately intensive CT supported by GM-CSF in ‘poor risk’ MDS gives promising results; the response rate is high for this disease, while the incidence of toxic death is low. GM-CSF appears to accelerate neutrophil recovery and probably reduces the incidence of infection.

Intensive chemotherapy with or without G-CSF in high risk myelodysplastic syndromes (MDS) or acute leukemia (AL) evolving from MDS: Randomized clinical study

In this prospective study, patients with ‘high risk’ primary MDS, namely RAEB or RAEBt, were treated with combination chemotherapy (CT) supported by GM-CSF. The induction CT consisted of idarubicin 6 mg/m2 days 1–3 and cytosine-arabinoside 200 mg/m2 in 12 h infusion, days 1–5. The GM-CSF 3 μg/kg s.c. was given on day 6 until the neutrophil count was 1 × 109/l. Postremission CT consisted of two similar courses. Patients not in remission after two courses of CT were considered as treatment failures. Twenty-two patients with a median age of 64 years, range 50–79 years (11 RAEB and 11 RAEBt) were evaluable. Twelve out of 22 patients (54.5%) achieved complete remission (CR) and four, partial remission. Six patients were resistant to treatment; there were two toxic deaths; seven patients achieved CR after the first course and five after two courses. The median time of neutrophil recovery to 1 × 109/l was day 15 (range 3–22) after the first course of treatment and day 14 (range 4–21) after the second. Thirteen out of 22 patients developed febrile episodes after the first course of treatment and nine after the second. The median duration of CR was 12 months. The median survival for CR patients was 24 months, for non-CR patients, 12 months; while survival for the whole population was 18 months.In conclusion, the results of this study indicate that the administration of moderately intensive CT supported by GM-CSF in ‘poor risk’ MDS gives promising results; the response rate is high for this disease, while the incidence of toxic death is low. GM-CSF appears to accelerate neutrophil recovery and probably reduces the incidence of infection.

Treatment of acute leukemia arising from myelodysplastic syndromes with oral idarubicin, etoposide, and 6-thioguanine

In this prospective study, patients with ‘high risk’ primary MDS, namely RAEB or RAEBt, were treated with combination chemotherapy (CT) supported by GM-CSF. The induction CT consisted of idarubicin 6 mg/m2 days 1–3 and cytosine-arabinoside 200 mg/m2 in 12 h infusion, days 1–5. The GM-CSF 3 μg/kg s.c. was given on day 6 until the neutrophil count was 1 × 109/l. Postremission CT consisted of two similar courses. Patients not in remission after two courses of CT were considered as treatment failures. Twenty-two patients with a median age of 64 years, range 50–79 years (11 RAEB and 11 RAEBt) were evaluable. Twelve out of 22 patients (54.5%) achieved complete remission (CR) and four, partial remission. Six patients were resistant to treatment; there were two toxic deaths; seven patients achieved CR after the first course and five after two courses. The median time of neutrophil recovery to 1 × 109/l was day 15 (range 3–22) after the first course of treatment and day 14 (range 4–21) after the second. Thirteen out of 22 patients developed febrile episodes after the first course of treatment and nine after the second. The median duration of CR was 12 months. The median survival for CR patients was 24 months, for non-CR patients, 12 months; while survival for the whole population was 18 months.In conclusion, the results of this study indicate that the administration of moderately intensive CT supported by GM-CSF in ‘poor risk’ MDS gives promising results; the response rate is high for this disease, while the incidence of toxic death is low. GM-CSF appears to accelerate neutrophil recovery and probably reduces the incidence of infection.